U.S. patent application number 10/871549 was filed with the patent office on 2005-06-30 for pharmaceutical formulations of amyloid inhibiting compounds.
This patent application is currently assigned to Neurochem (International) Limited. Invention is credited to Legore, Audley.
Application Number | 20050142191 10/871549 |
Document ID | / |
Family ID | 33545348 |
Filed Date | 2005-06-30 |
United States Patent
Application |
20050142191 |
Kind Code |
A1 |
Legore, Audley |
June 30, 2005 |
Pharmaceutical formulations of amyloid inhibiting compounds
Abstract
Therapeutic formulations and methods for inhibiting amyloid
deposition in a subject, whatever its clinical setting, are
described. Therapeutic formulations and methods for preventing or
treating amyloidosis and/or amyloid-related disease are also
described.
Inventors: |
Legore, Audley; (Chomedey,
CA) |
Correspondence
Address: |
LAHIVE & COCKFIELD, LLP.
28 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
Neurochem (International)
Limited
Walchwil
CH
|
Family ID: |
33545348 |
Appl. No.: |
10/871549 |
Filed: |
June 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60480984 |
Jun 23, 2003 |
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60512116 |
Oct 17, 2003 |
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60482214 |
Jun 23, 2003 |
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60482058 |
Jun 23, 2003 |
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60512135 |
Oct 17, 2003 |
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60480918 |
Jun 23, 2003 |
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60512017 |
Oct 17, 2003 |
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60480906 |
Jun 23, 2003 |
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60512047 |
Oct 17, 2003 |
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60480928 |
Jun 23, 2003 |
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60512018 |
Oct 17, 2003 |
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Current U.S.
Class: |
424/464 ;
514/553 |
Current CPC
Class: |
A61K 9/2846 20130101;
A61P 9/10 20180101; A61P 43/00 20180101; A61P 31/12 20180101; A61K
9/2886 20130101; A61P 27/02 20180101; A61P 31/00 20180101; A61P
31/04 20180101; A61K 9/2054 20130101; A61P 3/10 20180101; Y10S
514/974 20130101; A61P 31/22 20180101; A61K 31/185 20130101; A61P
7/04 20180101; A61P 21/00 20180101; A61P 3/00 20180101; A61P 1/00
20180101; A61K 9/20 20130101; A61P 25/00 20180101; A61P 25/28
20180101 |
Class at
Publication: |
424/464 ;
514/553 |
International
Class: |
A61K 031/185; A61K
009/20 |
Claims
1-6. (canceled)
7. A method of treating or preventing an amyloid-related disease in
a subject comprising administering to a subject a therapeutic
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance, such that the amyloid-related disease
is treated or prevented.
8-9. (canceled)
10. The method of claim 7, wherein the amyloid-related disease is
selected from the group consisting of Alzheimer's disease, cerebral
amyloid angiopathy, inclusion body myositis, macular degeneration,
Down's syndrome, Mild Cognitive Impairment, and hereditary cerebral
hemorrhage.
11. The method of claim 7, wherein the amyloid-related disease is
Alzheimer's disease type II diabetes.
12-14. (canceled)
15. The method of claim 7, wherein the therapeutic compound is a
substituted or unsubstituted alkylsulfonic acid, substituted or
unsubstituted alkylsulfuric acid, substituted or unsubstituted
alkylthiosulfonic acid, substituted or unsubstituted
alkylthiosulfuric acid, or a pharmaceutically acceptable salt
thereof.
16-19. (canceled)
20. The method of claim 7, wherein the therapeutic compound has the
following structure 16where Y is --NR.sup.aR.sup.b or
--SO.sub.3.sup.-X.sup.+, wherein n is an integer from 1 to 5;
X.sup.+ is hydrogen or a cationic group; and R.sup.a and R.sup.b
are each independently selected from the group consisting of
hydrogen, alkyl, aryl, or heterocyclyl, or R.sup.a and R.sup.b,
taken together with the nitrogen atom to which they are attached,
form a cyclic moiety having from 3 to 8 atoms in the ring.
21. (canceled)
22. The method of claim 7, wherein the therapeutic compound is
3-amino-1-propanesulfonic acid.
23. The method of claim 7, wherein the therapeutic formulation is
formulated as described in Example 1, Example 2, Example 3, or
Example 4.
24. The method of claim 7, wherein the therapeutic compound is
administered orally.
25-42. (canceled)
43. The method of claim 7, wherein the therapeutic compound is
administered with an agent selected from the group consisting of an
agent that modifies the release of the therapeutic compound, a
glidant/diluent, a filler, a binder/desintegrant, a lubricant, a
subcoat, a topcoat, an enteric coat, and any combination
thereof.
44-54. (canceled)
55. A pharmaceutical composition for treating or preventing an
amyloid-related disease comprising a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance, in an amount
sufficient to prevent or treat an amyloid-related disease in a
subject, and a pharmaceutically acceptable vehicle.
56. (canceled)
57. The pharmaceutical composition of claim 55, wherein the
amyloid-related disease is selected from the group consisting of
Alzheimer's disease, cerebral amyloid angiopathy, inclusion body
myositis, macular degeneration, Down's syndrome, Mild Cognitive
Impairment, and hereditary cerebral hemorrhage.
58. The pharmaceutical composition of claim 57 wherein the
amyloid-related disease is Alzheimer's disease diabetes.
59-62. (canceled)
63. The pharmaceutical composition of claim 55, wherein the
therapeutic compound is a substituted or unsubstituted
alkylsulfonic acid, substituted or unsubstituted alkylsulfuric
acid, substituted or unsubstituted alkylthiosulfonic acid,
substituted or unsubstituted alkylthiosulfuric acid, or a
pharmaceutically acceptable salt thereof.
64-67. (canceled)
68. The pharmaceutical composition of claim 55, wherein the
therapeutic compound has the following structure 17where Y is
--NR.sup.aR.sup.b or --SO.sub.3.sup.-X.sup.+, wherein n is an
integer from 1 to 5; X.sup.+ is hydrogen or a cationic group; and
R.sup.a and R.sup.b are each independently selected from the group
consisting of hydrogen, alkyl, aryl, or heterocyclyl, or R.sup.a
and R.sup.b, taken together with the nitrogen atom to which they
are attached, form a cyclic moiety having from 3 to 8 atoms in the
ring.
69. (canceled)
70. The pharmaceutical composition of claim 55, wherein the
therapeutic compound is 3-amino-1-propanesulfonic acid.
71. The pharmaceutical composition of claim 55, wherein the
therapeutic formulation is formulated as described in Example 1,
Example 2, Example 3, or Example 4.
72. The pharmaceutical composition of claim 70, wherein the
therapeutic formulation is formulated with an agent selected from
the group consisting of an agent that modifies the release of the
therapeutic compound, a glidant/diluent, a filler, a
binder/desintegrant, a lubricant, a subcoat, a topcoat, an enteric
coat, and any combination thereof.
73. The pharmaceutical composition of claim 72, wherein the agent
that modifies the release of the therapeutic compound is
hydroxypropylmethylcellulose (HPMC).
74. The pharmaceutical composition of claim 72, wherein the
glidant/diluent is silicated mycrocrystalline.
75. The pharmaceutical composition of claim 72, wherein the filler
is dibasic calcium phosphate.
76. The pharmaceutical composition of claim 72, wherein the
binder/desintegrant is Starch 1500.
77. The pharmaceutical composition of claim 72, wherein the
lubricant is stearic acid powder.
78. The pharmaceutical composition of claim 72, wherein the
lubricant is magnesium stearate.
79. The pharmaceutical composition of claim 72, wherein the subcoat
is Opadry.RTM. II White.
80. The pharmaceutical composition of claim 72, wherein the topcoat
is Opadry.RTM. II White or Opadry.RTM. Clear.
81. The pharmaceutical composition of claim 72, wherein the enteric
coat is Acryleze.RTM..
82-89. (canceled)
90. The method of claim 7, wherein the amyloid-related disease is
cerebral amyloid angiopathy.
91-101. (canceled)
102. A pharmaceutical formulation comprising greater than 5% by
weight of 3-amino-1-propanesulfonic acid.
103-108. (canceled)
109. The pharmaceutical formulation of claim 102 further comprising
greater than 1% by weight of an additional agent.
110-113. (canceled)
114. The pharmaceutical formulation of claim 109, wherein the
additional agent is an enteric-coating or an agent that modifies
the release of the therapeutic compound.
115-121. (canceled)
122. The method of claim 7 wherein the therapeutic compound is
formulated with an enteric-coating, or an agent that modifies the
release of the therapeutic compound.
123-125. (canceled)
126. A method of preventing, treating or inhibiting Alzheimer's
disease in a subject, comprising administering to the subject an
effective amount of a therapeutic formulation comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal intolerance, such that Alzheimer's disease is
prevented, treated, or inhibited.
127. A packaged pharmaceutical composition for treating Alzheimer's
disease in a subject, comprising a container holding a
therapeutically effective amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance; and instructions
for using the compound for treating Alzheimer's disease in a
subject.
128. The method of claim 126, wherein the therapeutic compound is
3-amino-1-propanesulfonic acid.
129. A pharmaceutical composition for preventing, treating or
inhibiting Alzheimer's disease in a subject comprising a
therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance, in an amount sufficient to prevent, treat or inhibit
Alzheimer's disease in a subject, and a pharmaceutically acceptable
vehicle.
130. The pharmaceutical composition of claim 129, wherein the
therapeutic compound is 3-amino-1-propanesulfonic acid.
131. The method of claim 7, wherein the therapeutic formulation
comprises a therapeutic compound having the formula
3-amino-1-propanesulfonate/X in an amount sufficient to prevent or
treat an amyloid-related disease, wherein X is a counter cation or
forms an ester with the sulfonate, wherein the ester or counter
cation includes alcohol radicals or positively charged atoms and
moieties, respectively, that do not significantly affect the
ability of the therapeutic formulation to reduce or prevent
gastrointestinal intolerance.
132. The pharmaceutical composition of claim 55, wherein the
therapeutic formulation comprises a therapeutic compound having the
formula 3-amino-1-propanesulfonate/X in an amount sufficient to
prevent or treat an amyloid-related disease, and a pharmaceutically
acceptable vehicle, wherein X is a counter cation or forms an ester
with the sulfonate, wherein the ester or counter cation includes
alcohol radicals or positively charged atoms and moieties,
respectively, which do not significantly affect the ability of the
therapeutic formulation to reduce or prevent gastrointestinal
intolerance.
133. The pharmaceutical composition of claim 55, wherein the
therapeutic compound is formulated with an enteric-coating or an
agent that modifies the release of the therapeutic compound.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application No. 60/480,984, filed Jun. 23, 2003, identified by
Attorney Docket No. NBI-152-1, and U.S. provisional patent
application No. 60/512,116, filed Oct. 17, 2003, identified by
Attorney Docket No. NBI-152-2, both entitled Pharmaceutical
Formulations of Amyloid-Inhibiting Compounds.
[0002] This application is related to U.S. provisional application
No. 60/436,379, filed Dec. 24, 2002, identified by Attorney Docket
No. NBI-154-1, entitled Combination Therapy for the Treatment of
Alzheimer's Disease, U.S. provisional application 60/482,214, filed
Jun. 23, 2003, identified by Attorney Docket No. NBI-154-2, U.S.
utility patent application Ser. No. 10/746,138, filed Dec. 24,
2003, identified by Attorney Docket No. NBI-154, and International
patent application no. PCT/CA2003/002011, identified by NBI-154PC
entitled Therapeutic Formulations for the Treatment of Beta-Amyloid
Related Diseases. This application is related to U.S. provisional
patent application No. 60/482,058, filed Jun. 23, 2003, identified
by Attorney Docket No. NBI-156-1, U.S. provisional patent
application No. 60/512,135, filed Oct. 17, 2003, identified by
Attorney Docket No. NBI-1156-2, both entitled Synthetic Process for
Preparing Compounds for Treating Amyloidosis, and U.S. application
Ser. No. ______, filed Jun. 18, 2004, identified by Attorney Docket
No. NBI-156, entitled Improved Pharmaceutical Drug Candidates and
Method for Preparation Thereof This application is also related to
U.S. provisional patent application No. 60/480,918, filed Jun. 23,
2003, identified by Attorney Docket No. NBI-149-1, U.S. provisional
application 60/512,017, filed Oct. 17, 2003, identified by Attorney
Docket No. NBI-149-2, and U.S. patent application Ser. No. ______,
filed Jun. 18, 2004, identified by Attorney Docket No. NBI-149
entitled Methods for Treating Protein Aggregation Disorders. This
application is also related to U.S. provisional patent application
No. 60/480,906, filed Jun. 23, 2003, identified by Attorney Docket
No. NBI-162-1, U.S. provisional patent application No. 60/512,047,
filed Oct. 17, 2003, identified by Attorney Docket No. NBI-162-2,
U.S. application Ser. No. ______, filed Jun. 18, 2004, identified
by Attorney Docket No. NBI-162A and U.S. application Ser. No.
______, filed Jun. 18, 2004, identified by Attorney Docket No.
NBI-162B, all entitled Methods and Compositions for Treating
Amyloid-Related Diseases; and U.S. provisional patent application
No. 60/480,928, also filed 23 Jun. 2003, identified by Attorney
Docket No. NBI-163-1, U.S. provisional patent application No.
60/512,018, filed Oct. 17, 2003, identified by Attorney Docket No.
NBI-163-2 and U.S. application Ser. No. ______, filed Jun. 18,
2004, identified by Attorney Docket No. NBI-163, all entitled
Methods and Compositions for the Treatment of Amyloid- and
Epileptogenesis-Associated Diseases; This application is also
related to Method for Treating Amyloidosis, U.S. patent application
Ser. No. 08/463,548, now U.S. Pat. No. 5,972,328, identified by
Attorney Docket No. NCI-003CP4.
[0003] The entire contents of each of the foregoing patent
applications and patents are expressly incorporated by reference in
their entirety including, without limitation, the specification,
claims, and abstract, as well as any figures, tables, or drawings
thereof.
BACKGROUND OF THE INVENTION
[0004] Amyloidosis refers to a pathological condition characterized
by the presence of amyloid fibrils. Amyloid is a generic term
referring to a group of diverse but specific protein deposits
(intracellular or extracellular) which are seen in a number of
different diseases. Though diverse in their occurrence, all amyloid
deposits have common morphologic properties, stain with specific
dyes (e.g., Congo red), and have a characteristic red-green
birefringent appearance in polarized light after staining. They
also share common ultrastructural features and common X-ray
diffraction and infrared spectra.
[0005] Amyloid-related diseases can either be restricted to one
organ or spread to several organs. The first instance is referred
to as "localized amyloidosis" while the second is referred to as
"systemic amyloidosis."
[0006] Some amyloid diseases can be idiopathic, but most of these
diseases appear as a complication of a previously existing
disorder. For example, primary amyloidosis (AL amyloid) can appear
without any other pathology or can follow plasma cell dyscrasia or
multiple myeloma.
[0007] Secondary amyloidosis is usually seen associated with
chronic infection (such as tuberculosis) or chronic inflammation
(such as rheumatoid arthritis). A familial form of secondary
amyloidosis is also seen in other types of familial amyloidosis,
e.g., Familial Mediterranean Fever (FMF). This familial type of
amyloidosis is genetically inherited and is found in specific
population groups. In both primary and secondary amyloidosis,
deposits are found in several organs and are thus considered
systemic amyloid diseases.
[0008] "Localized amyloidoses" are those that tend to involve a
single organ system. Different amyloids are also characterized by
the type of protein present in the deposit. For example,
neurodegenerative diseases such as scrapie, bovine spongiform
encephalitis, Creutzfeldt-Jakob disease, and the like are
characterized by the appearance and accumulation of a
protease-resistant form of a prion protein (referred to as AScr or
PrP-27) in the central nervous system. Similarly, Alzheimer's
disease, another neurodegenerative disorder, is characterized by
neuritic plaques and neurofibrillary tangles. In this case, the
amyloid plaques found in the parenchyma and the blood vessel is
formed by the deposition of fibrillar A.beta. amyloid protein.
Other diseases such as adult-onset diabetes (type II diabetes) are
characterized by the localized accumulation of amyloid fibrils in
the pancreas.
[0009] Once these amyloids have formed, there is no known, widely
accepted therapy or treatment which significantly dissolves amyloid
deposits in situ, prevents further amyloid deposition or prevents
the initiation of amyloid deposition.
[0010] Each amyloidogenic protein has the ability to undergo a
conformational change and to organize into .beta.-sheets and form
insoluble fibrils which may be deposited extracellularly or
intracellularly. Each amyloidogenic protein, although different in
amino acid sequence, has the same property of forming fibrils and
binding to other elements such as proteoglycan, amyloid P and
complement component. Moreover, each amyloidogenic protein has
amino acid sequences which, although different, show similarities
such as regions with the ability to bind to the glycosaminoglycan
(GAG) portion of proteoglycan (referred to as the GAG binding site)
as well as other regions which promote .beta.-sheet formation.
Proteoglycans are macromolecules of various sizes and structures
that are districuted almost everywhere in the body. They can be
found in the intracellular compartment, on the surface of cells,
and as part of the extracellular matrix. The basic structure of all
proteoglycans is comprised of a core protein and at least one, but
frequently more, polysaccharide chains (GAGs) attached to the core
protein. Many different GAGs have been discovered including
chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin,
and hyaluronan.
[0011] In specific cases, amyloid fibrils, once deposited, can
become toxic to the surrounding cells. For example, the A.beta.
fibrils organized as senile plaques have been shown to be
associated with dead neuronal cells, dystrophic neurites,
astrocytosis, and microgliosis in patients with Alzheimer's
disease. When tested in vitro, oligomeric (soluble) as well as
fibrillar A.beta. peptide was shown to be capable of triggering an
activation process of microglia (brain macrophages), which would
explain the presence of microgliosis and brain inflammation found
in the brain of patients with Alzheimer's disease. Both oligomeric
and fibrillar A.beta. peptide can also induce neuronal cell death
in vitro. See, e.g., M P Lambert, et al., Proc. Natl. Acad. Sci.
USA 95, 6448-53 (1998).
[0012] In another type of amyloidosis seen in patients with type II
diabetes, the amyloidogenic protein IAPP, when organized in
oligomeric forms or in fibrils, has been shown to induce
.beta.-islet cell toxicity in vitro. Hence, appearance of IAPP
fibrils in the pancreas of type II diabetic patients contributes to
the loss of the .beta. islet cells (Langerhans) and organ
dysfunction which can lead to insulinemia.
[0013] Another type of amyloidosis is related to .beta..sub.2
microglobulin and is found in long-term hemodialysis patients.
Patients undergoing long term hemodialysis will develop
.beta..sub.2-microglobulin fibrils in the carpal tunnel and in the
collagen rich tissues in several joints. This causes severe pains,
joint stiffness and swelling.
[0014] Amyloidosis is also characteristic of Alzheimer's disease.
Alzheimer's disease is a devastating disease of the brain that
results in progressive memory loss leading to dementia, physical
disability, and death over a relatively long period of time. With
the aging populations in developed countries, the number of
Alzheimer's patients is reaching epidemic proportions.
[0015] People suffering from Alzheimer's disease develop a
progressive dementia in adulthood, accompanied by three main
structural changes in the brain: diffuse loss of neurons in
multiple parts of the brain; accumulation of intracellular protein
deposits termed neurofibrillary tangles; and accumulation of
extracellular protein deposits termed amyloid or senile plaques,
surrounded by misshapen nerve terminals (dystrophic neurites) and
activated microglia (microgliosis and astrocytosis). A main
constituent of these amyloid plaques is the amyloid-.beta. peptide
(A.beta.), a 39-43 amino-acid protein that is produced through
cleavage of the .beta.-amyloid precursor protein (APP). Extensive
research has been conducted on the relevance of A.beta. deposits in
Alzheimer's disease, see, e.g., Selkoe, Trends in Cell Biology 8,
447-453 (1998). AD naturally arises from the metabolic processing
of the amyloid precursor protein ("APP") in the endoplasmic
reticulum ("ER"), the Golgi apparatus, or the endosomal-lysosomal
pathway, and most is normally secreted as a 40 ("A.beta.1-40") or
42 ("A.beta.1-42") amino acid peptide (Selkoe, Annu. Rev. Cell
Biol. 10, 373-403 (1994)). A role for A.beta. as a primary cause
for Alzheimer's disease is supported by the presence of
extracellular A.beta. deposits in senile plaques of Alzheimer's
disease, the increased production of A.beta. in cells harboring
mutant Alzheimer's disease associated genes, e.g., amyloid
precursor protein, presenilin I and presenilin II; and the toxicity
of extracellular soluble (oligomeric) or fibrillar A.beta. to cells
in culture. See, e.g., Gervais, Eur. Biopharm. Review, 40-42
(Autumn 2001); May, DDT 6, 459-62 (2001). Although symptomatic
treatments exist for Alzheimer's disease, this disease cannot be
prevented or cured at this time.
[0016] Alzheimer's disease is characterized by diffuse and neuritic
plaques, cerebral angiopathy, and neurofibrillary tangles. Plaque
and blood vessel amyloid is believed to be formed by the deposition
of insoluble A.beta. amyloid protein, which may be described as
diffuse or fibrillary. Both soluble oligomeric A.beta. and
fibrillar A.beta. are also believed to be neurotoxic and
inflammatory.
[0017] Another type of amyloidosis is cerebral amyloid angiopathy
(CAA). CAA is the specific deposition of amyloid .beta. fibrils in
the walls of leptomingeal and cortical arteries, arterioles and
veins. It is commonly associated with Alzheimer's disease, Down's
syndrome and normal aging, as well as with a variety of familial
conditions related to stroke or dementia (see Frangione et al.,
Amyloid: J. Protein Folding Disord. 8, Suppl. 1, 36-42 (2001)).
[0018] Presently available therapies for treatment of
.beta.-amyloid diseases are almost entirely symptomatic, providing
only temporary or partial clinical benefit. Although some
pharmaceutical agents have been described that offer partial
symptomatic relief, no comprehensive pharmacological therapy is
currently available for the prevention or treatment of, for
example, Alzheimer's disease.
SUMMARY OF THE INVENTION
[0019] This invention provides methods, compositions, and
formulations that are useful in the treatment of amyloidosis. The
methods of the invention involve administering to a subject a
therapeutic composition or formulation that inhibits amyloid
deposition. Accordingly, the compositions and methods of the
invention are useful for inhibiting amyloidosis disorders in which
amyloid deposition occurs. The methods of the invention may be used
therapeutically to treat amyloidosis or may be used
prophylactically in a subject susceptible to amyloidosis.
[0020] In one aspect, the methods of the present invention are
based, at least in part, on inhibiting an interaction between an
amyloidogenic protein and a constituent of a basement membrane to
inhibit amyloid deposition. In particular embodiments, the
constituent of the basement membrane is a glycoprotein or
proteoglycan, preferably agrin, perlecan, or heparan sulfate
proteoglycan. A therapeutic compound used in the method of the
invention can interfere with binding of a basement membrane
constituent to a target binding site on an amyloidogenic protein,
thereby inhibiting amyloid deposition. In other embodiments, a
therapeutic compound used in the method of the invention can
enhance clearance of amyloid .beta. from the brain, thereby
inhibiting amyloid deposition. In other embodiments, a therapeutic
compound used in the method of the invention can inhibit
neurodegeneration or cellular toxicity induced by amyloid (e.g., by
soluble or insoluble amyloid, e.g., fibrils, by amyloid deposition
and/or by amyloid-.beta., as described herein).
[0021] In preferred aspects, the invention relates to the use of
alkylsulfonic acids in the treatment of amyloid-related
diseases.
[0022] Accordingly, in one aspect, the invention is directed to a
method for inhibiting amyloid deposition in a subject comprising
administering to the subject an effective amount of a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance, such
that amyloid deposition is inhibited.
[0023] In another aspect, the invention pertains to a method of
treating or preventing an amyloid-related disease, e.g.,
A.beta.-related disease, in a subject, comprising administering to
a subject a therapeutic amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance, such that the
amyloid-related disease is treated or prevented.
[0024] In an additional aspect, the invention is a method for
inhibiting amyloid deposition in a subject comprising administering
to the subject an effective amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance, such that the
therapeutic compound inhibits an interaction between an
amyloidogenic protein and a constituent of a basement membrane to
inhibit amyloid deposition.
[0025] Another aspect of the invention involves a method for
inhibiting amyloid deposition in a subject comprising administering
to the subject an effective amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance, such that the
therapeutic compound inhibits neurodegeneration or cellular
toxicity induced by amyloid (e.g., by soluble or insoluble amyloid,
e.g., fibrils, by amyloid deposition and/or by amyloid-.beta., as
described herein).
[0026] In another aspect, the invention is directed to a method for
inhibiting amyloid deposition in a subject comprising administering
to the subject an effective amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance, such that the
therapeutic compound enhances clearance of amyloid .beta. from the
brain.
[0027] In yet another aspect, the invention pertains to a method
for inhibiting amyloid deposition in a subject comprising orally
administering to the subject an effective amount of a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance.
[0028] An additional aspect of the invention is a pharmaceutical
composition for inhibiting amyloid deposition in a subject
comprising a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance, in an amount sufficient to inhibit
amyloid deposition in a subject, and a pharmaceutically acceptable
vehicle.
[0029] In another aspect, the invention is directed to a
pharmaceutical composition for treating amyloidosis comprising a
therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance, in an amount sufficient to inhibit amyloid deposition
in a subject, and a pharmaceutically acceptable vehicle.
[0030] In another aspect, the present invention pertains to a
pharmaceutical composition for treating or preventing an
amyloid-related disease, e.g., A.beta.-related disease, comprising
a therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance, in an amount sufficient to prevent or treat an
amyloid-related disease in a subject, and a pharmaceutically
acceptable vehicle.
[0031] In yet another aspect, the invention pertains to a method
for reducing amyloid deposits in a subject having amyloid deposits,
the method comprising administering to the subject an effective
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance, such that amyloid deposits are
reduced in the subject.
[0032] Another aspect of the invention is directed to a method for
inhibiting the binding of a chemokine to a glycosaminoglycan in a
subject comprising administering to the subject a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance, such
that the binding of a chemokine to a glycosaminoglycan is
inhibited.
[0033] Yet another aspect of the invention is directed to a method
for modulating interaction between a bacterium and a
glycosaminoglycan in a human comprising administering to the human
an effective amount of a therapeutic formulation comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal intolerance.
[0034] In an additional aspect, the invention pertains to a method
for treating a bacterial infection in a human comprising
administering to the human an effective amount of a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance.
[0035] In another aspect, the invention is a method for modulating
interaction between a virus and a glycosaminoglycan in a subject
comprising administering to the subject an effective amount of a
therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance.
[0036] Another aspect of the invention is a method for treating a
viral infection in a subject comprising administering to the
subject a therapeutic formulation comprising an effective amount of
a therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance.
[0037] Yet another aspect of the invention is directed to a method
of preventing, treating or inhibiting cerebral amyloid angiopathy
in a subject, comprising administering an effective amount of a
therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance.
[0038] In an additional aspect, the invention pertains to a method
of preventing, treating or inhibiting cerebral amyloid angiopathy,
comprising contacting a blood vessel wall cell with a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance, such
that cerebral amyloid angiopathy is prevented, treated, or
inhibited.
[0039] In another aspect, the invention pertains to a method of
preventing, treating or inhibiting cerebral amyloid angiopathy,
comprising contacting a blood vessel wall cell with a therapeutic
compound of a therapeutic formulation, formulated to significantly
reduce or prevent gastrointestinal intolerance, such that cerebral
amyloid angiopathy is prevented, treated, or inhibited.
[0040] An additional aspect of the present invention is directed to
a method of preventing, treating or inhibiting Alzheimer's disease
in a subject, comprising administering to the subject an effective
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance.
[0041] An additional aspect of the present invention is directed to
a method of preventing, treating or inhibiting Alzheimer's disease
in a subject, comprising administering to the subject an effective
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance, such that Alzheimer's disease is
prevented, treated, or inhibited.
[0042] In another aspect, the invention is directed to a packaged
pharmaceutical composition for inhibiting amyloid deposition in a
subject, comprising a container holding a therapeutically effective
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance; and instructions for using the
compound for inhibiting amyloid deposition in a subject.
[0043] In yet another aspect, the invention pertains to a packaged
pharmaceutical composition for treating amyloidosis in a subject,
comprising a container holding a therapeutically effective amount
of a therapeutic formulation comprising a therapeutic compound
formulated to significantly reduce or prevent gastrointestinal
intolerance; and instructions for using the compound for treating
amyloidosis in a subject.
[0044] In yet another aspect, the invention pertains to a packaged
pharmaceutical composition for treating Alzheimer's disease in a
subject, comprising a container holding a therapeutically effective
amount of a therapeutic formulation comprising a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance; and instructions for using the
compound for treating Alzheimer's disease in a subject.
[0045] Another aspect of the invention is a packaged pharmaceutical
composition for treating a viral infection, comprising a container
holding a therapeutically effective amount of a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance; and
instructions for using the compound for treating the viral
infection.
[0046] In an additional aspect, the invention is directed to a
packaged pharmaceutical composition for treating a bacterial
infection, comprising a container holding a therapeutically
effective amount of a therapeutic formulation comprising a
therapeutic compound formulated to significantly reduce or prevent
gastrointestinal intolerance; and instructions for using the
therapeutic compound for treating the bacterial infection.
[0047] In another aspect, the invention pertains to a packaged
pharmaceutical composition for inhibiting the binding of a
chemokine to a glycosaminoglycan, comprising a container holding a
therapeutically effective amount of a therapeutic formulation
comprising a therapeutic compound formulated to significantly
reduce or prevent gastrointestinal intolerance; and instructions
for using the therapeutic compound for inhibiting the binding of a
chemokine to a glycosaminoglycan.
[0048] In yet another aspect, the invention pertains to method of
making a therapeutic formulation comprising combining a
therapeutically effective amount of a therapeutic compound and a
pharmaceutically acceptable vehicle, wherein the therapeutic
formulation is formulated to significantly reduce or prevent
gastrointestinal intolerance.
[0049] An additional aspect of the invention is directed to a
pharmaceutical formulation comprising greater than 5% by weight of
3-amino-1-propanesulfonic acid.
[0050] In another aspect, the invention is a pharmaceutical
formulation comprising a therapeutic compound and greater than 1%
by weight of an additional agent.
[0051] In yet another aspect, the invention pertains to a method
for inhibiting amyloid deposition in a subject comprising
administering to the subject an effective amount of a therapeutic
formulation comprising a therapeutic compound formulated with an
enteric-coating, such that amyloid deposition is inhibited.
[0052] Another aspect of the invention is directed to a method for
inhibiting amyloid deposition in a subject comprising administering
to the subject an effective amount of a therapeutic formulation
comprising a therapeutic compound formulated with an agent that
modifies the release of the therapeutic compound, such that amyloid
deposition is inhibited.
[0053] Additionally, a further aspect of the invention is a
pharmaceutical composition for inhibiting amyloid deposition in a
subject comprising a therapeutic compound formulated with an
enteric-coating, such that amyloid deposition is inhibited.
[0054] In another aspect, the present invention pertains to a
pharmaceutical composition for inhibiting amyloid deposition in a
subject comprising a therapeutic compound formulated with an agent
that modifies the release of the therapeutic compound, such that
amyloid deposition is inhibited.
[0055] In yet another aspect, the invention pertains to a method of
formulating a gastrointestinal intolerance enhanced pharmaceutical
composition comprising: combining a pre-selected therapeutic
compound with a pharmaceutically acceptable carrier, wherein the
therapeutic compound is pre-selected for its ability to
significantly reduce or prevent gastrointestinal intolerance,
forming a gastrointestinal intolerance enhanced pharmaceutical
composition.
[0056] In an additional aspect, the invention is directed to a
method for preventing or treating amyloid-related disease in a
subject comprising administering to the subject an effective amount
of a therapeutic formulation comprising a therapeutic compound
formulated with an enteric-coating, such that amyloid-related
disease is prevented or treated.
[0057] Another aspect of the invention is a method for preventing
or treating amyloid-related disease in a subject comprising
administering to the subject an effective amount of a therapeutic
formulation comprising a therapeutic compound formulated with an
agent that modifies the release of the therapeutic compound, such
that amyloid-related disease is prevented or treated.
[0058] In another aspect, the invention is directed to a
pharmaceutical composition for preventing or treating
amyloid-related disease in a subject comprising a therapeutic
compound formulated with an enteric-coating.
[0059] In yet another aspect, the invention pertains to a
pharmaceutical composition for preventing or treating
amyloid-related disease in a subject comprising a therapeutic
compound formulated with an agent that modifies the release of the
therapeutic compound.
DETAILED DESCRIPTION OF THE INVENTION
[0060] This invention pertains to methods, compositions, and
formulations useful for treating amyloidosis. The methods of the
invention involve administering to a subject a therapeutic
formulation comprising a therapeutic compound that inhibits amyloid
deposition. In particular, the present invention therefore relates
to the use of therapeutic formulations, e.g., comprising
alkylsulfonic acids, in the prevention or treatment of
amyloid-related diseases, including, inter alia, Alzheimer's
disease, cerebral amyloid angiopathy, inclusion body myositis,
macular degeneration, Down's syndrome, Mild Cognitive Impairment,
and type II diabetes.
[0061] I. Amyloid-Related Diseases
[0062] The present invention relates to the use of pharmaceutical
compositions or formulations comprising therapeutic compounds
useful in the treatment of amyloid-related diseases. Many
amyloid-related diseases are known, and others doubtless exist.
[0063] AA (Reactive) Amyloidosis
[0064] Generally, AA amyloidosis is a manifestation of a number of
diseases that provoke a sustained acute phase response. Such
diseases include chronic inflammatory disorders, chronic local or
systemic microbial infections, and malignant neoplasms. The most
common form of reactive or secondary (AA) amyloidosis is seen as
the result of long-standing inflammatory conditions. For example,
patients with Rheumatoid Arthritis or Familial Mediterranean Fever
(which is a genetic disease) can develop AA amyloidosis. The terms
"AA amyloidosis" and "secondary (AA) amyloidosis" are used
interchangeably.
[0065] AA fibrils are generally composed of 8,000 Dalton fragments
(AA peptide or protein) formed by proteolytic cleavage of serum
amyloid A protein (ApoSAA), a circulating apolipoprotein which is
mainly synthesized in hepatocytes in response to such cytokines as
IL-1, IL-6 and TNF. Once secreted, ApoSAA is complexed with HDL.
Deposition of AA fibrils can be widespread in the body, with a
preference for parenchymal organs. The kidneys are usually a
deposition site, and the liver and the spleen may also be affected.
Deposition is also seen in the heart, gastrointestinal tract, and
the skin.
[0066] Underlying diseases which can lead to the development of AA
amyloidosis include, but are not limited to inflammatory diseases,
such as rheumatoid arthritis, juvenile chronic arthritis,
ankylosing spondylitis, psoriasis, psoriatic arthropathy, Reiter's
syndrome, Adult Still's disease, Behcet's syndrome, and Crohn's
disease. AA deposits are also produced as a result of chronic
microbial infections, such as leprosy, tuberculosis,
bronchiectasis, decubitus ulcers, chronic pyelonephritis,
osteomyelitis, and whipple's disease. Certain malignant neoplasms
can also result in AA fibril amyloid deposits. These include such
conditions as Hodgkin's lymphoma, renal carcinoma, carcinomas of
gut, lung and urogenital tract, basal cell carcinoma, and hairy
cell leukemia. Other underlying conditions that may be associated
with AA amyloidosis are Castleman's disease and Schnitzler's
syndrome.
[0067] AL Amyloidoses (Primary Amyloidosis)
[0068] AL amyloid deposition is generally associated with almost
any dyscrasia of the B lymphocyte lineage, ranging from malignancy
of plasma cells (multiple myeloma) to benign monoclonal gammopathy.
At times, the presence of amyloid deposits may be a primary
indicator of the underlying dyscrasia. AL amyloidosis is also
described in detail in Current Drug Targets, 2004, 5 159-171.
[0069] Fibrils of AL amyloid deposits are composed of monoclonal
immunoglobulin light chains or fragments thereof. More
specifically, the fragments are derived from the N-terminal region
of the light chain (kappa or lambda) and contain all or part of the
variable (V.sub.L) domain thereof. Deposits generally occur in the
mesenchymal tissues, causing peripheral and autonomic neuropathy,
carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy,
arthropathy of large joints, immune dyscrasias, myelomas, as well
as occult dyscrasias. However, it should be noted that almost any
tissue, particularly visceral organs such as the kidney, liver,
spleen and heart, may be involved.
[0070] Hereditary Systemic Amyloidoses
[0071] There are many forms of hereditary systemic amyloidoses.
Although they are relatively rare conditions, adult onset of
symptoms and their inheritance patterns (usually autosomal
dominant) lead to persistence of such disorders in the general
population. Generally, the syndromes are attributable to point
mutations in the precursor protein leading to production of variant
amyloidogenic peptides or proteins. Table 1 summarizes the fibril
composition of exemplary forms of these disorders.
1TABLE 1 Fibril Composition of Exemplary Amyloid-Related Diseases
Genetic Fibril Peptide/Protein Variant Clinical Syndrome ATTR
protein from Transthyretin Met30, many Familial amyloid
polyneuropathy (FAP), and fragments others (Mainly peripheral
nerves) ATTR protein from Transthyretin Thr45, Ala60, Cardiac
involvement predominant without and fragments Ser84, Met111,
neuropathy, familial amyloid polyneuropathy, Ile122 senile systemic
amyloidosis, Tenosynovium N-terminal fragment of Arg26 Familial
amyloid polyneuropathy (FAP), Apolipoprotein A1 (apoAI) (mainly
peripheral nerves) N-terminal fragment of Arg26, Arg50,
Ostertag-type, non-neuropathic (predominantly Apoliproprotein A1
(AapoAI) Arg 60, others visceral involvement) AapoAII from
Apolipoprotein AII Familial amyloidosis Lysozyme (Alys) Thr56,
His67 Ostertag-type, non-neuropathic (predominantly visceral
involvement) Fibrogen alpha chain fragment Leu554, Val Cranial
neuropathy with lattic corneal 526 dystrophy Gelsolin fragment
(Agel) Asn187, Cranial neuropathy with lattice corneal Tyr187
dystrophy Cystatin C fragment (ACys) Glu68 Hereditary cerebral
hemorrhage (cerebral amyloid angiopathy) - Icelandic type
.beta.-amyloid protein (A.beta.) derived from Gln693 Hereditary
cerebral hemorrhage (cerebral Amyloid Precursor Protein (APP)
amyloid angiopathy) - Dutch type .beta.-amyloid protein (A.beta.)
derived from Ile717, Phe717, Familial Alzheimer's Disease Amyloid
Precursor Protein (APP) Gly717 .beta.-amyloid protein (A.beta.)
derived from Gln 618 Alzheimer's disease, Down's syndrome, Amyloid
Precursor Protein (APP), hereditary cerebral hemorrhage with e.g.,
bPP 695 amyloidosis, Dutch type .beta.-amyloid protein (A.beta.)
derived from Asn670, Familial Dementia - probably Alzheimer's
Amyloid Precursor Protein (APP) Leu671 Disease Prion Protein (PrP,
APrP.sup.SC) derived Leu102, Familial Creutzfeldt-Jakob disease;
from Prp precursor protein (51-91 Val167,
Gerstmann-Strussler-Scheinker syndrome insert) Asn178, (hereditary
spongiform encephalopathies, Lys200 prion diseases) AA derived from
Serum amyloid A Familial Mediterranean fever, predominant protein
(ApoSAA) renal involvement (autosomal recessive) AA derived from
Serum amyloid A Muckle-Well's syndrome, nephropathy, protein
(ApoSAA) deafness, urticaria, limb pain Unknown Cardiomyopathy with
persistent atrial standstill Unknown Cutaneous deposits (bullous,
papular, pustulodermal) AH amyloid protein, derived from A.gamma.I
Myeloma associated amyloidosis immunoglobulin heavy chain (gamma I)
ACal amyloid protein from (Pro) calcitonin Medullary carcinomas of
the thyroid (pro)calcitonin AANF amyloid protein from atrial
Isolated atrial amyloid natriuretic factor Apro from Prolactin
Prolactinomas Abri/ADan from ABri peptide British and Danish
familial Dementia Data derived from Tan SY, Pepys MB. Amyloidosis.
Histopathology, 25(5), 403-414 (Nov 1994), WHO/IUIS Nomenclature
Subcommittee, Nomenclature of Amyloid and Amyloidosis. Bulletin of
the World Health Organisation 1993; 71: 10508; and Merlini et al.,
Clin Chem Lab Med 2001; 39(11): 1065-75.
[0072] The data provided in Table 1 are exemplary and are not
intended to limit the scope of the invention. For example, more
than 40 separate point mutations in the transthyretin gene have
been described, all of which give rise to clinically similar forms
of familial amyloid polyneuropathy.
[0073] In general, any hereditary amyloid disorder can also occur
sporadically, and both hereditary and sporadic forms of a disease
present with the same characteristics with regard to amyloid. For
example, the most prevalent form of secondary AA amyloidosis occurs
sporadically, e.g. as a result of ongoing inflammation, and is not
associated with Familial Mediterranean Fever. Thus general
discussion relating to hereditary amyloid disorders below can also
be applied to sporadic amyloidoses.
[0074] Transthyretin (TTR) is a 14 kiloDalton protein that is also
sometimes referred to as prealbumin. It is produced by the liver
and choroid plexus, and it functions in transporting thyroid
hormones and vitamin A. At least 50 variant forms of the protein,
each characterized by a single amino acid change, are responsible
for various forms of familial amyloid polyneuropathy. For example,
substitution of proline for leucine at position 55 results in a
particularly progressive form of neuropathy; substitution of
methionine for leucine at position 111 resulted in a severe
cardiopathy in Danish patients.
[0075] Amyloid deposits isolated from heart tissue of patients with
systemic amyloidosis have revealed that the deposits are composed
of a heterogeneous mixture of TTR and fragments thereof,
collectively referred to as ATTR, the full length sequences of
which have been characterized. ATTR fibril components can be
extracted from such plaques and their structure and sequence
determined according to the methods known in the art (e.g.,
Gustavsson, A., et al., Laboratory Invest. 73: 703-708, 1995;
Kametani, F., et al., Biochem. Biophys. Res. Commun. 125: 622-628,
1984; Pras, M., et al., PNAS 80: 539-42, 1983).
[0076] Persons having point mutations in the molecule
apolipoprotein AI (e.g., Gly.fwdarw.Arg26; Trp.fwdarw.Arg50;
Leu.fwdarw.Arg60) exhibit a form of amyloidosis ("Ostertag type")
characterized by deposits of the protein apolipoprotein AI or
fragments thereof (AApoAI). These patients have low levels of high
density lipoprotein (HDL) and present with a peripheral neuropathy
or renal failure.
[0077] A mutation in the alpha chain of the enzyme lysozyme (e.g.,
Ile.fwdarw.Thr56 or Asp.fwdarw.His57) is the basis of another form
of Ostertag-type non-neuropathic hereditary amyloid reported in
English families. Here, fibrils of the mutant lysozyme protein
(Alys) are deposited, and patients generally exhibit impaired renal
function. This protein, unlike most of the fibril-forming proteins
described herein, is usually present in whole (unfragmented) form
(Benson, M. D., et al. CIBA Fdn. Symp. 199: 104-131, 1996).
[0078] Immunoglobulin light chains tend to form aggregates in
various morphologies, including fibrillar (e.g., AL amyloidosis and
AH amyloidosis), granular (e.g., light chain deposition disease
(LCDD), heavy chain deposition disease (HCDD), and light-heavy
chain deposition disease (LHCDD)), crystalline (e.g., Acquired
Farconi's Syndome), and microtubular (e.g., Cryoglobulinemia). AL
and AH amyloidosis is indicated by the formation of insoluble
fibrils of immunoglobulin light chains and heavy chain,
respectively, and/or their fragments. In AL fibrils, lambda
(.lambda.) chains such as .lambda. VI chains (.lambda.6 chains),
are found in greater concentrations than kappa (.kappa.) chains.
XIII chains are also slightly elevated. Merlini et al., CLIN CHEM
LAB MED 39(11):1065-75 (2001). Heavy chain amyloidosis (AH) is
generally characterized by aggregates of gamma chain amyloid
proteins of the IgG1 subclass. Eulitz et al., PROC NATL ACAD SCI
USA 87: 6542-46 (1990).
[0079] Comparison of amyloidogenic to non-amyloidogenic light
chains has revealed that the former can include replacements or
substitutions that appear to destabilize the folding of the protein
and promote aggregation. AL and LCDD have been distinguished from
other amyloid diseases due to their relatively small population
monoclonal light chains, or fragments thereof, which are
manufactured by neoplastic expansion of an antibody-producing B
cell. AL aggregates typically are well-ordered fibrils of lambda
chains. LCDD aggregates are relatively amorphous aggregations of
both kappa and lambda chains, with a majority being kappa, in some
cases .kappa.IV. Bellotti et al., JOURNAL OF STRUCTURAL BIOLOGY 13:
280-89 (2000). Comparison of amyloidogenic and non-amyloidogenic
heavy chains in patients having AH amyloidosis has revealed missing
and/or altered components. Eulitz et al., PROC NATL ACAD SCI USA
87: 6542-46 (1990) (pathogenic heavy chain characterized by
significantly lower molecular mass than non-amyloidogenic heavy
chains); and Solomon et al. AM J HEMAT 45(2) 171-6 (1994)
(amyloidogenic heavy chain characterized as consisting solely of
the VH-D portion of the non-amyloidogenic heavy chain).
[0080] Accordingly, potential methods of detecting and monitoring
treatment of subjects having or at risk of having AL, LCDD, AH, and
the like, include but are not limited to immunoassaying plasma or
urine for the presence or depressed deposition of amyloidogenic
light or heavy chains, e.g., amyloid .lambda., amyloid .kappa.,
amyloid .kappa.IV, amyloid .gamma., or amyloid .gamma.1.
[0081] Brain Amyloidosis
[0082] The most frequent type of amyloid in the brain is composed
primarily of A.beta. peptide fibrils, resulting in dementia
associated with sporadic (non-hereditary) Alzheimer's disease. In
fact, the incidence of sporadic Alzheimer's disease greatly exceeds
forms shown to be hereditary. Nevertheless, fibril peptides forming
plaques are very similar in both types. Brain amyloidosis includes
those diseases, conditions, pathologies, and other abnormalities of
the structure or function of the brain, including components
thereof, in which the causative agent is amyloid. The area of the
brain affected in an amyloid-related disease may be the stroma
including the vasculature or the parenchyma including functional or
anatomical regions, or neurons themselves. A subject need not have
received a definitive diagnosis of a specifically recognized
amyloid-related disease. The term "amyloid-related disease"
includes brain amyloidosis.
[0083] Amyloid-.beta. peptide ("A.beta.") is a 39-43 amino acid
peptide derived by proteolysis from a large protein known as Beta
Amyloid Precursor Protein (".beta.APP"). Mutations in .beta.APP
result in familial forms of Alzheimer's disease, Down's syndrome,
cerebral amyloid angiopathy, and senile dementia, characterized by
cerebral deposition of plaques composed of A.beta. fibrils and
other components, which are described in further detail below.
Known mutations in APP associated with Alzheimer's disease occur
proximate to the cleavage sites of .beta. or .gamma.-secretase, or
within A.beta.. For example, position 717 is proximate to the site
of gamma-secretase cleavage of APP in its processing to A.beta.,
and positions 670/671 are proximate to the site of .beta.-secretase
cleavage. Mutations at any of these residues may result in
Alzheimer's disease, presumably by causing an increase in the
amount of the 42/43 amino acid form of A.beta. generated from APP.
The familial form of Alzheimer's disease represents only 10% of the
subject population. Most occurrences of Alzheimer's disease are
sporadic cases where APP and A.beta. do not possess any mutation.
The structure and sequence of A.beta. peptides of various lengths
are well known in the art. Such peptides can be made according to
methods known in the art, or extracted from the brain according to
known methods (e.g., Glenner and Wong, Biochem. Biophys. Res. Comm.
129, 885-90 (1984); Glenner and Wong, Biochem. Biophys. Res. Comm.
122, 1131-35 (1984)). In addition, various forms of the peptides
are commercially available. APP is expressed and constitutively
catabolized in most cells. The dominant catabolic pathway appears
to be cleavage of APP within the A.beta. sequence by an enzyme
provisionally termed .alpha.-secretase, leading to release of a
soluble ectodomain fragment known as APPs.alpha.. This cleavage
precludes the formation of A.beta. peptide. In contrast to this
non-amyloidogenic pathway, APP can also be cleaved by enzymes known
as .beta.- and .gamma.-secretase at the N- and C-termini of the
A.beta., respectively, followed by release of A.beta. into the
extracellular space. To date, BACE has been identified as
.beta.-secretase (Vasser, et al., Science 286: 735-741, 1999) and
presenilins have been implicated in .gamma.-secretase activity (De
Strooper, et al., Nature 391, 387-90 (1998)). The 39-43 amino acid
A.beta. peptide is produced by sequential proteolytic cleavage of
the amyloid precursor protein (APP) by the .beta. and .gamma.
secretases enzyme. Although A.beta.40 is the predominant form
produced, 5-7% of total A.beta. exists as A.beta.42 (Cappai et al.,
Int. J. Biochem. Cell Biol. 31. 885-89 (1999)).
[0084] The length of the A.beta. peptide appears to dramatically
alter its biochemical/biophysical properties. Specifically, the
additional two amino acids at the C-terminus of A.beta.42 are very
hydrophobic, presumably increasing the propensity of A.beta.42 to
aggregate. For example, Jarrett, et al. demonstrated that A.beta.42
aggregates very rapidly in vitro compared to A.beta.40, suggesting
that the longer forms of A.beta. may be the important pathological
proteins that are involved in the initial seeding of the neuritic
plaques in Alzheimer's disease (Jarrett, et al., Biochemistry 32,
4693-97 (1993); Jarrett, et al., Ann. N.Y. Acad. Sci. 695, 144-48
(1993)). This hypothesis has been further substantiated by the
recent analysis of the contributions of specific forms of A.beta.
in cases of genetic familial forms of Alzheimer's disease ("FAD").
For example, the "London" mutant form of APP (APPV717I) linked to
FAD selectively increases the production of A.beta. 42/43 forms
versus A.beta. 40 (Suzuki, et al., Science 264, 1336-40 (1994))
while the "Swedish" mutant form of APP (APPK670N/M671L) increases
levels of both A.beta.40 and A.beta.42/43 (Citron, et al., Nature
360, 672-674 (1992); Cai, et al., Science 259, 514-16, (1993)).
Also, it has been observed that FAD-linked mutations in the
Presenilin-1 ("PS1") or Presenilin-2 ("PS2") genes will lead to a
selective increase in A.beta.42/43 production but not A.beta.40
(Borchelt, et al., Neuron 17, 1005-13 (1996)). This finding was
corroborated in transgenic mouse models expressing PS mutants that
demonstrate a selective increase in brain A.beta.42 (Borchelt, op
cit.; Duff, et al., Neurodegeneration 5(4), 293-98 (1996)). Thus
the leading hypothesis regarding the etiology of Alzheimer's
disease is that an increase in A.beta.42 brain concentration due to
an increased production and release of A.beta.42 or a decrease in
clearance (degradation or brain clearance) is a causative event in
the disease pathology.
[0085] Multiple mutation sites in either A.beta. or the APP gene
have been identified and are clinically associated with either
dementia or cerebral hemorrhage. Exemplary CAA disorders include,
but are not limited to, hereditary cerebral hemorrhage with
amyloidosis of Icelandic type (HCHWA-I); the Dutch variant of HCHWA
(HCHWA-D; a mutation in A.beta.); the Flemish mutation of A.beta.;
the Arctic mutation of A.beta.; the Italian mutation of A.beta.;
the Iowa mutation of A.beta.; familial British dementia; and
familial Danish dementia. CAA may also be sporadic.
[0086] As used herein, the terms ".beta. amyloid,"
"amyloid-.beta.," and the like refer to amyloid .beta. proteins or
peptides, amyloid .beta. precursor proteins or peptides,
intermediates, and modifications and fragments thereof, unless
otherwise specifically indicated. In particular, "A.beta." refers
to any peptide produced by proteolytic processing of the APP gene
product, especially peptides which are associated with amyloid
pathologies, including A.beta.1-39, A.beta.1-40, A.beta.1-41,
A.beta.1-42, and A.beta.1-43. For convenience of nomenclature,
"A.beta.1-42" may be referred to herein as "A.beta.(1-42)" or
simply as "A.beta.42" or "A.beta.42" (and likewise for any other
amyloid peptides discussed herein). As used herein, the terms
".beta. amyloid," "amyloid-.beta.," and are synonymous.
[0087] Unless otherwise specified, the term "amyloid" refers to
amyloidogenic proteins, peptides, or fragments thereof which can be
soluble (e.g., monomeric or oligomeric) or insoluble (e.g., having
fibrillary structure or in amyloid plaque). See, e.g., M P Lambert,
et al., Proc. Nat'l Acad. Sci. USA 95, 6448-53 (1998).
"Amyloidosis" or "amyloid disease" or "amyloid-related disease"
refers to a pathological condition characterized by the presence of
amyloid fibers. "Amyloid" is a generic term referring to a group of
diverse but specific protein deposits (intracellular or
extracellular) which are seen in a number of different diseases.
Though diverse in their occurrence, all amyloid deposits have
common morphologic properties, stain with specific dyes (e.g.,
Congo red), and have a characteristic red-green birefringent
appearance in polarized light after staining. They also share
common ultrastructural features and common X-ray diffraction and
infrared spectra.
[0088] Gelsolin is a calcium binding protein that binds to
fragments and actin filaments. Mutations at position 187 (e.g.,
Asp.fwdarw.Asn; Asp.fwdarw.Tyr) of the protein result in a form of
hereditary systemic amyloidosis, usually found in patients from
Finland, as well as persons of Dutch or Japanese origin. In
afflicted individuals, fibrils formed from gelsolin fragments
(Agel), usually consist of amino acids 173-243 (68 kDa
carboxyterminal fragment) and are deposited in blood vessels and
basement membranes, resulting in corneal dystrophy and cranial
neuropathy which progresses to peripheral neuropathy, dystrophic
skin changes and deposition in other organs. (Kangas, H., et al.
Human Mol. Genet. 5(9): 1237-1243, 1996).
[0089] Other mutated proteins, such as mutant alpha chain of
fibrinogen (AfibA) and mutant cystatin C (Acys) also form fibrils
and produce characteristic hereditary disorders. AfibA fibrils form
deposits characteristic of a nonneuropathic hereditary amyloid with
renal disease; Acys deposits are characteristic of a hereditary
cerebral amyloid angiopathy reported in Iceland (Isselbacher,
Harrison's Principles of Internal Medicine, McGraw-Hill, San
Francisco, 1995; Benson, et al.). In at least some cases, patients
with cerebral amyloid angiopathy (CAA) have been shown to have
amyloid fibrils containing a non-mutant form of cystatin C in
conjunction with amyloid beta protein (Nagai, A., et al. Molec.
Chem. Neuropathol. 33: 63-78, 1998).
[0090] Certain forms of prion disease are now considered to be
heritable, accounting for up to 15% of cases, which were previously
thought to be predominantly infectious in nature. (Baldwin, et al.,
in Research Advances in Alzheimer's Disease and Related Disorders,
John Wiley and Sons, New York, 1995). In hereditary and sporadic
prion disorders, patients develop plaques composed of abnormal
isoforms of the normal prion protein (PrP.sup.Sc).
[0091] A predominant mutant isoform, PrP.sup.Sc, also referred to
as AScr, differs from the normal cellular protein in its resistance
to protease degradation, insolubility after detergent extraction,
deposition in secondary lysosomes, post-translational synthesis,
and high .beta.-pleated sheet content. Genetic linkage has been
established for at least five mutations resulting in
Creutzfeldt-Jacob disease (CJD), Gerstmann-Straussler-Scheinker
syndrome (GSS), and fatal familial insomnia (FFI). (Baldwin, supra)
Methods for extracting fibril peptides from scrapie fibrils,
determining sequences and making such peptides are known in the art
(e.g., Beekes, M., et al. J. Gen. Virol. 76: 2567-76, 1995).
[0092] For example, one form of GSS has been linked to a PrP
mutation at codon 102, while telencephalic GSS segregates with a
mutation at codon 117. Mutations at codons 198 and 217 result in a
form of GSS in which neuritic plaques characteristic of Alzheimer's
disease contain PrP instead of A.beta. peptide. Certain forms of
familial CJD have been associated with mutations at codons 200 and
210; mutations at codons 129 and 178 have been found in both
familial CJD and FFI. (Baldwin, supra).
[0093] Cerebral Amyloidosis
[0094] Local deposition of amyloid is common in the brain,
particularly in elderly individuals. The most frequent type of
amyloid in the brain is composed primarily of A.beta. peptide
fibrils, resulting in dementia or sporadic (non-hereditary)
Alzheimer's disease. The most common occurrences of cerebral
amyloidosis are sporadic and not familial. For example, the
incidence of sporadic Alzheimer's disease and sporadic CAA greatly
exceeds the incidence of familial AD and CAA. Moreover, sporadic
and familial forms of the disease cannot be distinguished from each
other (they differ only in the presence or absence of an inherited
genetic mutation); for example, the clinical symptoms and the
amyloid plaques formed in both sporadic and familial AD are very
similar, if not identical.
[0095] Cerebral amyloid angiopathy (CAA) refers to the specific
deposition of amyloid fibrils in the walls of leptomingeal and
cortical arteries, arterioles and veins. It is commonly associated
with Alzheimer's disease, Down's syndrome and normal aging, as well
as with a variety of familial conditions related to stroke or
dementia (see Frangione et al., Amyloid: J. Protein Folding Disord.
8, Suppl. 1, 36-42 (2001)). CAA can occur sporadically or be
hereditary.
[0096] Senile Systemic Amyloidosis
[0097] Amyloid deposition, either systemic or focal, increases with
age. For example, fibrils of wild type transthyretin (TTR) are
commonly found in the heart tissue of elderly individuals. These
may be asymptomatic, clinically silent, or may result in heart
failure. Asymptomatic fibrillar focal deposits may also occur in
the brain (A.beta.), corpora amylacea of the prostate (.beta..sub.2
microglobulin), joints and seminal vesicles.
[0098] Dialysis-Related Amyloidosis (DRA)
[0099] Plaques composed of .beta..sub.2 microglobulin
(.beta..sub.2M) fibrils commonly develop in patients receiving long
term hemodialysis or peritoneal dialysis. .beta..sub.2
microglobulin is a 11.8 kiloDalton polypeptide and is the light
chain of Class I MHC antigens, which are present on all nucleated
cells. Under normal circumstances, .beta..sub.2M is usually
distributed in the extracellular space unless there is an impaired
renal function, in which case .beta..sub.2M is transported into
tissues where it polymerizes to form amyloid fibrils. Failure of
clearance such as in the case of impaired renal function, leads to
deposition in the carpal tunnel and other sites (primarily in
collagen-rich tissues of the joints). Unlike other fibril proteins,
.beta..sub.2M molecules are not produced by cleavage of a longer
precursor protein and are generally present in unfragmented form in
the fibrils. (Benson, supra). Retention and accumulation of this
amyloid precursor has been shown to be the main pathogenic process
underlying DRA. DRA is characterized by peripheral joint
osteoarthropathy (e.g., joint stiffness, pain, swelling, etc.).
Isoforms of .beta..sub.2M, glycated .beta..sub.2M, or polymers of
.beta..sub.2M in tissue are the most amyloidogenic form (as opposed
to native .beta..sub.2M). Unlike other types of amyloidosis,
.beta..sub.2M is confined largely to osteoarticular sites. Visceral
depositions are rare. Occasionally, these deposits may involve
blood vessels and other important anatomic sites.
[0100] Despite improved dialysis methods for removal of
.beta..sub.2M, the majority of patients have plasmatic
.beta..sub.2M concentrations that remain dramatically higher than
normal. These elevated .beta..sub.2M concentrations generally lead
to Diabetes-Related Amyloidosis (DRA) and cormorbidities that
contribute to mortality.
[0101] Islet Amyloid Polypeptide and Diabetes
[0102] Islet hyalinosis (amyloid deposition) was first described
over a century ago as the presence of fibrous protein aggregates in
the pancreas of patients with severe hyperglycemia (Opie, E L., J
Exp. Med. 5: 397-428, 1901). Today, islet amyloid, composed
predominantly of islet amyloid polypeptide (LAPP), or amylin, is a
characteristic histopathological marker in over 90% of all cases of
Type II diabetes (also known as Non-Insulin Dependent Diabetes, or
NIDDM). These fibrillar accumulations result from the aggregation
of the islet amyloid polypeptide (IAPP) or amylin, which is a 37
amino acid peptide, derived from a larger precursor peptide, called
pro-IAPP.
[0103] IAPP is co-secreted with insulin in response to .beta.-cell
secretagogues. This pathological feature is not associated with
insulin-dependent (Type I) diabetes and is a unifying
characteristic for the heterogeneous clinical phenotypes diagnosed
as NIDDM (Type II diabetes).
[0104] Longitudinal studies in cats and immunocytochemical
investigations in monkeys have shown that a progressive increase in
islet amyloid is associated with a dramatic decrease in the
population of insulin-secreting .beta.-cells and increased severity
of the disease. More recently, transgenic studies have strengthened
the relationship between IAPP plaque formation and .beta.-cell
apoptosis and dysfunction, indicating that amyloid deposition is a
principal factor in increasing severity of Type II diabetes.
[0105] IAPP has also been shown to induce .beta.-islet cell
toxicity in vitro, indicating that appearance of IAPP fibrils in
the pancreas of Type II or Type I diabetic patients (post-islet
transplantation) could contribute to the loss of the .beta.-cell
islets (Langerhans) and organ dysfunction. In patients with Type II
diabetes, the accumulation of pancreatic IAPP leads to formation of
oligomeric IAPP, leading to a buildup of IAPP-amyloid as insoluble
fibrous deposits which eventually destroys the insulin-producing
.beta. cells of the islet, resulting in .beta. cell depletion and
failure (Westermark, P., Grimelius, L., Acta Path. Microbiol.
Scand., sect. A. 81: 291-300, 1973; de Koning, E J P., et al.,
Diabetologia 36: 378-384, 1993; and Lorenzo, A., et al., Nature
368: 756-760, 1994). Accumulation of IAPP as fibrous deposits can
also have an impact on the ratio of pro-IAPP to IAPP normally found
in plasma by increasing this ratio due to the trapping of IAPP in
deposits. Reduction of .beta. cell mass can be manifested by
hyperglycemia and insulinemia. This .beta.-cell mass loss can lead
to a need for insulin therapy.
[0106] Diseases caused by the death or malfunctioning of a
particular type or types of cells can be treated by transplanting
into the patient healthy cells of the relevant type of cell. This
approach has been used for Type I diabetes patients. Often
pancreatic islet cells from a donor are cultured in vitro prior to
transplantation, to allow them to recover after the isolation
procedure or to reduce their immunogenicity. However, in many
instances islet cell transplantation is unsuccessful, due to death
of the transplanted cells. One reason for this poor success rate is
IAPP, which organizes into toxic oligomers. Toxic effects may
result from intracellular and extracellular accumulation of fibril
oligomers. The IAPP oligomers can form fibrils and become toxic to
the cells in vitro. In addition, IAPP fibrils are likely to
continue to grow after the cells are transplanted and cause death
or dysfunction of the cells. This may occur even when the cells are
from a healthy donor and the patient receiving the transplant does
not have a disease that is characterized by the presence of
fibrils. For example, compounds of the present invention may also
be used in preparing tissues or cells for transplantation according
to the methods described in International Patent Application (PCT)
number WO 01/003680.
[0107] The compounds of the invention may also stabilize the ratio
of the concentrations of Pro-IAPP/IAPP, pro-Insulin/Insulin and
C-peptide levels. In addition, as biological markers of efficacy,
the results of the different tests, such as the arginine-insulin
secretion test, the glucose tolerance test, insulin tolerance and
sensitivity tests, could all be used as markers of reduced
.beta.-cell mass and/or accumulation of amyloid deposits. Such
class of drugs could be used together with other drugs targeting
insulin resistance, hepatic glucose production, and insulin
secretion. Such compounds might prevent insulin therapy by
preserving .beta.-cell function and be applicable to preserving
islet transplants.
[0108] Hormone-Derived Amyloidoses
[0109] Endocrine organs may harbor amyloid deposits, particularly
in aged individuals. Hormone-secreting tumors may also contain
hormone-derived amyloid plaques, the fibrils of which are made up
of polypeptide hormones such as calcitonin (medullary carcinoma of
the thyroid), and atrial natriuretic peptide (isolated atrial
amyloidosis). Sequences and structures of these proteins are well
known in the art.
[0110] Miscellaneous Amyloidoses
[0111] There are a variety of other forms of amyloid disease that
are normally manifest as localized deposits of amyloid. In general,
these diseases are probably the result of the localized production
or lack of catabolism of specific fibril precursors or a
predisposition of a particular tissue (such as the joint) for
fibril deposition. Examples of such idiopathic deposition include
nodular AL amyloid, cutaneous amyloid, endocrine amyloid, and
tumor-related amyloid. Other amyloid-related diseases include those
described in Table 1, such as familial amyloid polyneuropathy
(FAP), senile systemic amyloidosis, Tenosynovium, familial
amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial
neuropathy, hereditary cerebral hemorrhage, familial dementia,
chronic dialysis, familial Creutzfeldt-Jakob disease;
Gerstmann-Strussler-Scheink- er syndrome, hereditary spongiform
encephalopathies, prion diseases, familial Mediterranean fever,
Muckle-Well's syndrome, nephropathy, deafness, urticaria, limb
pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign
monoclonal gammopathy, maccoglobulinaemia, myeloma associated
amyloidosis, medullary carcinomas of the thyroid, isolated atrial
amyloid, and diabetes.
[0112] The compounds of the invention may be administered
therapeutically or prophylactically to treat diseases associated
with amyloid fibril formation, aggregation or deposition,
regardless of the clinical setting. The compounds of the invention
may act to ameliorate the course of an amyloid-related disease
using any of the following mechanisms, such as, for example but not
limited to: slowing the rate of amyloid fibril formation or
deposition; lessening the degree of amyloid deposition; inhibiting,
reducing, or preventing amyloid fibril formation; inhibiting
amyloid induced inflammation; enhancing the clearance of amyloid
from, for example, the brain; or protecting cells from amyloid
induced (oligomers or fibrillar) toxicity.
[0113] In an embodiment, the compounds/formulations of the
invention may be administered therapeutically or prophylactically
to treat diseases associated with amyloid-.beta. fibril formation,
aggregation or deposition. The compounds of the invention may act
to ameliorate the course of an amyloid-.beta. related disease using
any of the following mechanisms (this list is meant to be
illustrative and not limiting): slowing the rate of amyloid-.beta.
fibril formation or deposition; lessening the degree of
amyloid-.beta. deposition; inhibiting, reducing, or preventing
amyloid-.beta. fibril formation; inhibiting neurodegeneration or
cellular toxicity induced by amyloid-.beta.; inhibiting
amyloid-.beta. induced inflammation; enhancing the clearance of
amyloid-.beta. from the brain; or favoring greater catabolism of
A.beta..
[0114] Compounds of the invention may be effective in controlling
amyloid-.beta. deposition either following their entry into the
brain (following penetration of the blood brain barrier) or from
the periphery. When acting from the periphery, a compound may alter
the equilibrium of A.beta. between the brain and the plasma so as
to favor the exit of A.beta. from the brain. An increase in the
exit of A.beta. from the brain would result in a decrease in
A.beta. brain concentration and therefore favor a decrease in
A.beta. deposition. In addition, compounds that penetrate the brain
may control deposition by acting directly on brain A.beta., e.g.,
by maintaining it in a non-fibrillar form or favoring its clearance
from the brain. The compounds may slow down APP processing; may
increase degradation of A.beta. fibrils by macrophages or by
neuronal cells; or may decrease A.beta. production by activated
microglia. These compounds could also prevent A.beta. in the brain
from interacting with the cell surface and therefore prevent
neurotoxicity, neurodegeneration, or inflammation.
[0115] In a preferred embodiment, the method is used to treat
Alzheimer's disease (e.g., sporadic or familial AD). The method can
also be used prophylactically or therapeutically to treat other
clinical occurrences of amyloid-.beta. deposition, such as in
Down's syndrome individuals and in patients with cerebral amyloid
angiopathy ("CAA"), hereditary cerebral hemorrhage, or early
Alzheimer's disease.
[0116] In another embodiment, the method is used to treat mild
cognitive impairment. Mild Cognitive Impairment ("MCI") is a
condition characterized by a state of mild but measurable
impairment in thinking skills, which is not necessarily associated
with the presence of dementia. MCI frequently, but not necessarily,
precedes Alzheimer's disease.
[0117] Additionally, abnormal accumulation of APP and of
amyloid-.beta. protein in muscle fibers has been implicated in the
pathology of sporadic inclusion body myositis (IBM) (Askanas, V.,
et al. (1996) Proc. Natl. Acad. Sci. USA 93: 1314-1319; Askanas, V.
et al. (1995) Current Opinion in Rheumatology 7: 486-496).
Accordingly, the compounds of the invention can be used
prophylactically or therapeutically in the treatment of disorders
in which amyloid-beta protein is abnormally deposited at
non-neurological locations, such as treatment of IBM by delivery of
the compounds to muscle fibers.
[0118] Additionally, it has been shown that A.beta. is associated
with abnormal extracellular deposits, known as drusen, that
accumulate along the basal surface of the retinal pigmented
epithelium in individuals with age-related macular degeneration
(ARMD). ARMD is a cause of irreversible vision loss in older
individuals. It is believed that A.beta. deposition could be an
important component of the local inflammatory events that
contribute to atrophy of the retinal pigmented epithelium, drusen
biogenesis, and the pathogenesis of ARMD (Johnson, et al., Proc.
Natl. Acad. Sci. USA 99 (18), 11830-5 (2002)).
[0119] In another embodiment, the invention also relates to a
method of treating or preventing an amyloid-related disease in a
subject (preferably a human) comprising administering to the
subject a therapeutic amount of a compound according to the
following Formulae or otherwise described herein, such that amyloid
fibril formation or deposition, neurodegeneration, or cellular
toxicity is reduced or inhibited. In another embodiment, the
invention relates to a method of treating or preventing an
amyloid-related disease in a subject (preferably a human)
comprising administering to the subject a therapeutic amount of a
compound according to the following Formulae or otherwise described
herein, such that cognitive function is improved or stabilized or
further deterioration in cognitive function is prevented, slowed,
or stopped in patients with brain amyloidosis, e.g., Alzheimer's
disease, Down's syndrome or cerebral amyloid angiopathy. These
compounds can also improve quality of daily living in these
subjects.
[0120] The therapeutic compounds of the invention may treat
amyloidosis related to type II diabetes by, for example,
stabilizing glycemia, preventing or reducing the loss of .beta.
cell mass, reducing or preventing hyperglycemia due to loss of
.beta. cell mass, and modulating (e.g., increasing or stabilizing)
insulin production. The compounds of the invention may also
stabilize the ratio of the concentrations of pro-IAPP/IAPP.
[0121] The therapeutic compounds of the invention may treat AA
(secondary) amyloidosis and/or AL (primary) amyloidosis, by
stabilizing renal function, decreasing proteinuria, increasing
creatinine clearance (e.g., by at least 50% or greater or by at
least 100% or greater), or by leading to remission of chronic
diarrhea, or weight gain (e.g., 10% or greater).
[0122] II. Methods of the Invention
[0123] In one embodiment, the invention includes a method for
inhibiting amyloid deposition in a subject comprising administering
to the subject an effective amount of a therapeutic formulation
comprising a therapeutic compound as described herein, such that
amyloid deposition is inhibited. Accordingly, in another
embodiment, the invention pertains to a method of treating or
preventing an amyloid-related disease, e.g., A.beta.-related
disease, in a subject comprising administering to a subject a
therapeutic amount of a therapeutic formulation comprising a
therapeutic compound of the invention.
[0124] The formulations of the invention may be administered
therapeutically or prophylactically to treat diseases associated
with amyloid-.beta. fibril formation, aggregation or deposition.
The formulations of the invention may act to ameliorate the course
of an amyloid-.beta. related disease using any of the following
mechanisms (this list is meant to be illustrative and not
limiting): slowing the rate of amyloid-.beta. fibril formation or
deposition; lessening the degree of amyloid-.beta. deposition;
inhibiting, reducing, or preventing amyloid-.beta. fibril
formation; inhibiting neurodegeneration or cellular toxicity
induced by amyloid-.beta.; inhibiting amyloid-.beta. induced
inflammation; or enhancing the clearance of amyloid-.beta. from the
brain.
[0125] The formulations of the invention may be effective in
controlling amyloid-.beta. deposition either following their entry
into the brain (following penetration of the blood brain barrier)
or from the periphery. Without wishing to be bound by theory, when
acting from the periphery, the compound of a formulation of the
invention may alter the equilibrium of A.beta. between the brain
and the plasma so as to favor the exit of A.beta. from the brain.
An increase in the exit of A.beta. from the brain would result in a
decrease in A.beta. brain concentration and therefore favor a
decrease in A.beta. deposition. Alternatively, the compounds of a
formulation of the invention that penetrate the brain could control
deposition by acting directly on brain A.beta., e.g., by
maintaining it in a non-fibrillar form or favoring its clearance
from the brain, or protecting brain cells from the detrimental
effect of A.beta.. In another embodiment, the compound may also
prevent the amyloid protein, in its soluble, oligomeric form or in
its fibrillar form, from binding or adhering to a cell surface and
causing cell damage or toxicity.
[0126] In a particular embodiment, the method is used to treat
Alzheimer's disease (e.g., sporadic or familial AD). The method can
also be used prophylactically or therapeutically to treat other
clinical occurrences of amyloid-.beta. deposition, such as in
Down's syndrome individuals and in patients with cerebral amyloid
angiopathy ("CAA") or hereditary cerebral hemorrhage.
[0127] In certain embodiments, the therapeutic formulation of the
invention is capable of inhibiting an interaction between an
amyloidogenic protein and a constituent of a basement membrane,
e.g., a glycoprotein or a proteoglycan, to thus inhibit amyloid
deposition. The ability of a therapeutic compound of the invention
to inhibit an interaction between an amyloidogenic protein and a
glycoprotein or proteoglycan constituent of a basement membrane can
be assessed by an in vitro binding assay, such as the mass
spectroscopy assay described herein (Example 5) or in U.S. Pat. No.
5,164,295, which is hereby expressly incorporated herein by
reference in its entirety.
[0128] The present invention relates to a method for inhibiting
amyloid deposition in a subject comprising administering to the
subject an effective amount of a therapeutic formulation as
described herein, the therapeutic formulation comprising a
therapeutic compound that comprises at least one sulfonate group
covalently attached to a substituted or unsubstituted aromatic or
aliphatic molecule.
[0129] In another embodiment, the invention includes a method for
inhibiting the binding of a chemokine to a glycosaminoglycan
comprising administering a therapeutic formulation comprising a
therapeutic compound as described herein.
[0130] In yet another embodiment, the invention relates to a method
for modulating interaction between a bacterium and a
glycosaminoglycan in a human comprising administering to the human
a therapeutic formulation comprising a therapeutic compound as
described herein. Accordingly, the present invention also pertains
to a method for treating a bacterial infection in a human, the
method comprising administering to the human a therapeutic
formulation comprising a therapeutic compound of the invention. In
a specific embodiment, the invention is a method for treating a
subject afflicted with Chlamydia comprising administering to the
subject a therapeutic formulation comprising a therapeutic compound
as described herein.
[0131] In an additional embodiment, the invention includes a method
for modulating interaction between a virus and a glycosaminoglycan
in a subject comprising administering to the subject a therapeutic
formulation comprising a therapeutic compound as described herein.
More generally, another embodiment of the invention is a method for
treating a viral infection in a subject comprising administering to
the subject a therapeutic formulation comprising a therapeutic
compound of the invention. In a specific embodiment, the invention
is a method for treating a subject afflicted with HSV comprising
administering to the subject a therapeutic formulation comprising a
therapeutic compound as described herein.
[0132] Additionally, one embodiment of the invention is a method
for reducing amyloid deposits in a subject having amyloid deposits,
the method comprising administering to the subject an effective
amount of a therapeutic formulation comprising a therapeutic
compound as described herein, such that amyloid deposits are
reduced in the subject.
[0133] Another embodiment of the invention pertains to a method of
preventing, treating or inhibiting cerebral amyloid angiopathy in a
subject, comprising administering a therapeutic formulation
comprising a therapeutic compound of the invention to the subject.
Furthermore, the invention includes a method of preventing,
treating, or inhibiting cerebral amyloid angiopathy, comprising
contacting a blood vessel wall cell with a therapeutic formulation
comprising a therapeutic compound of the invention, such that
cerebral amyloid angiopathy is prevented, treated, or inhibited. In
addition, the invention includes a method of preventing, treating,
or inhibiting cerebral amyloid angiopathy, comprising contacting a
blood vessel wall cell with a therapeutic compound of a therapeutic
formulation of the invention, such that cerebral amyloid angiopathy
is prevented, treated, or inhibited.
[0134] The language "inhibition of amyloid deposition" includes
reducing, preventing or stopping of amyloid formation, e.g.,
fibrillogenesis, inhibiting or slowing down of further amyloid
deposition in a subject with amyloidosis, e.g., already having
amyloid deposits, and reducing or reversing amyloid fibrillogenesis
or deposits in a subject with ongoing amyloidosis. For example, the
extent of the inhibition of amyloid deposition is contemplated by
the instant application as a range, which can include, for example,
substantially complete elimination of amyloid deposition or
reduction of amyloid deposition. Inhibition of amyloid deposition
is determined relative to an untreated subject, or relative to the
treated subject prior to treatment, or, e.g., determined by
clinically measurable improvement in pancreatic function in a
diabetic patient, or in the case of a patient with brain
amyloidosis, e.g., an Alzheimer's or cerebral amyloid angiopathy
patient, stabilization of cognitive function or prevention of a
further decrease in cognitive function (i.e., preventing, slowing,
or stopping disease progression), or improvement of parameters such
as the concentration of A.beta. or tau in the CSF. In certain
embodiments, amyloid deposition may be inhibited by, for example,
inhibiting an interaction between an amyloidogenic protein and a
constituent of basement membrane, enhancing clearance of amyloid
.beta. from the brain, or inhibiting neurodegeneration or cellular
toxicity induced by amyloid (e.g., by soluble or insoluble amyloid,
e.g., fibrils, by amyloid deposition and/or by amyloid-.beta., as
described herein), or protecting brain cells from the detrimental
effect of A.beta..
[0135] The language "basement membrane" refers to an extracellular
matrix comprising glycoproteins and proteoglycans, including
laminin, collagen type IV, fibronectin, agrin, perlecan, and
heparan sulfate proteoglycan (HSPG). In one embodiment, amyloid
deposition is inhibited by interfering with an interaction between
an amyloidogenic protein and a sulfated glycosaminoglycan such as
HSPG. Sulfated glycosaminoglycans are known to be present in all
types of amyloids (see Snow, A. D., et al. Lab. Invest. 56, 120-123
(1987)) and amyloid deposition and HSPG deposition occur
coincidentally in animal models of amyloidosis (see Snow, A. D., et
al., Lab. Invest. 56, 665-675 (1987)).
[0136] As used herein, "treatment" of a subject includes the
application or administration of a composition of the invention to
a subject, or application or administration of a composition of the
invention to a cell or tissue from a subject, who has a
amyloid-related disease or condition, has a symptom of such a
disease or condition, or is at risk of (or susceptible to) such a
disease or condition, with the purpose of curing, healing,
alleviating, relieving, altering, remedying, ameliorating,
improving, or affecting the disease or condition, the symptom of
the disease or condition, or the risk of (or susceptibility to) the
disease or condition. The term "treating" refers to any indicia of
success in the treatment or amelioration of an injury, pathology or
condition, including any objective or subjective parameter such as
abatement; remission; diminishing of symptoms or making the injury,
pathology or condition more tolerable to the subject; slowing in
the rate of degeneration or decline; making the final point of
degeneration less debilitating; improving a subject's physical or
mental well-being; or, in some situations, preventing the onset of
dementia. The treatment or amelioration of symptoms can be based on
objective or subjective parameters; including the results of a
physical examination, a psychiatric evaluation, or a cognition test
such as CDR, MMSE, ADAS-Cog, or another test known in the art. For
example, the methods of the invention successfully treat a
subject's dementia by slowing the rate of or lessening the extent
of cognitive decline.
[0137] In one embodiment, the term "treating" includes maintaining
a subject's CDR rating at its base line rating or at 0. In another
embodiment, the term treating includes decreasing a subject's CDR
rating by about 0.25 or more, about 0.5 or more, about 1.0 or more,
about 1.5 or more, about 2.0 or more, about 2.5 or more, or about
3.0 or more. In another embodiment, the term "treating" also
includes reducing the rate of the increase of a subject's CDR
rating as compared to historical controls. In another embodiment,
the term includes reducing the rate of increase of a subject's CDR
rating by about 5% or more, about 10% or more, about 20% or more,
about 25% or more, about 30% or more, about 40% or more, about 50%
or more, about 60% or more, about 70% or more, about 80% or more,
about 90% or more, or about 100%, of the increase of the historical
or untreated controls.
[0138] In another embodiment, the term "treating" also includes
maintaining a subject's score on the MMSE. The term "treating"
includes increasing a subject's MMSE score by about 1, about 2,
about 3, about 4, about 5, about 7.5, about 10, about 12.5, about
15, about 17.5, about 20, or about 25 points. The term also
includes reducing the rate of the decrease of a subject's MMSE
score as compared to historical controls. In another embodiment,
the term includes reducing the rate of decrease of a subject's MMSE
score may be about 5% or less, about 10% or less, about 20% or
less, about 25% or less, about 30% or less, about 40% or less,
about 50% or less, about 60% or less, about 70% or less, about 80%
or less, about 90% or less or about 100% or less, of the decrease
of the historical or untreated controls.
[0139] In yet another embodiment, the term "treating" includes
maintaining a subject's score on the ADAS-Cog. The term "treating"
includes decreasing a subject's ADAS-Cog score by about 1 point or
greater, by about 2 points or greater, by about 3 points or
greater, by about 4 points or greater, by about 5 points or
greater, by about 7.5 points or greater, by about 10 points or
greater, by about 12.5 points or greater, by about 15 points or
greater, by about 17.5 points or greater, by about 20 points or
greater, or by about 25 points or greater. The term also includes
reducing the rate of the increase of a subject's ADAS-Cog score as
compared to historical controls. In another embodiment, the term
includes reducing the rate of increase of a subject's ADAS-Cog
score by about 5% or more, about 10% or more, about 20% or more,
about 25% or more, about 30% or more, about 40% or more, about 50%
or more, about 60% or more, about 70% or more, about 80% or more,
about 90% or more or about 100% of the increase of the historical
or untreated controls.
[0140] In another embodiment, the term "treating," for example, for
AA or AL amyloidosis, includes an increase in serum creatinine
clearance, e.g., an increase of creatinine clearance of 10% or
greater, 20% or greater, 50% or greater, 80% or greater, 90% or
greater, 100% or greater, 150% or greater, 200% or greater. The
term "treating" also may induce remission of nephrotic syndrome
(NS). It may also include remission of chronic diarrhea and/or a
gain in boday weight, e.g., by 10% or greater, 15% or greater, or
20% or greater.
[0141] Without wishing to be bound by theory, in some aspects the
pharmaceutical compositions of the invention contain a compound
that prevents or inhibits amyloid fibril formation, either in the
brain or other organ of interest (acting locally) or throughout the
entire body (acting systemically). Pharmaceutical compositions of
the invention may be effective in controlling amyloid deposition
either following their entry into the brain (following penetration
of the blood brain barrier) or from the periphery. When acting from
the periphery, a compound of a pharmaceutical composition may alter
the equilibrium of amyloidogenic peptide between the brain and the
plasma to favor the exit of amyloidogenic peptide from the brain.
It may also favor clearance (or catabolism) of the amyloid protein
(soluble), and then prevent amyloid fibril formation and deposition
due to a reduction of the amyloid protein pool in a specific organ,
e.g., liver, spleen, pancreas, kidney, joints, brain, etc. An
increase in the exit of amyloidogenic peptide from the brain would
result in a decrease in amyloidogenic peptide brain concentration,
and therefore, favor a decrease in amyloidogenic peptide
deposition. In particular, an agent may lower the levels of amyloid
.beta. peptides, e.g., both A.beta.40 and A.beta.42 in the CSF and
the plasma, or the agent may lower the levels of amyloid .beta.
peptides, e.g., A.beta.40 and A.beta.42 in the CSF and increase it
in the plasma. Alternatively, compounds that penetrate the brain
could control deposition by acting directly on brain amyloidogenic
peptide e.g., by maintaining it in a non-fibrillar form or favoring
its clearance from the brain, by increasing its degradation in the
brain, or protecting brain cells from the detrimental effect of
amyloidogenic peptide. An agent can also cause a decrease of the
concentration of the amyloid protein (i.e., in a specific organ so
that the critical concentration needed to trigger amyloid fibril
formation or deposition is not reached). Furthermore, the compounds
described herein may inhibit or reduce an interaction between
amyloid and a cell surface constituent, for example, a
glycosaminoglycan or proteoglycan constituent of a basement
membrane. The compounds may also prevent an amyloid peptide from
binding or adhering to a cell surface, a process that is known to
cause cell damage or toxicity. Similarly, the compounds may block
amyloid-induced cellular toxicity or microglial activation or
amyloid-induced neurotoxicity, or inhibit amyloid induced
inflammation. The compounds may also reduce the rate or amount of
amyloid aggregation, fibril formation, or deposition, or the
compounds may lessen the degree of amyloid deposition. The
foregoing mechanisms of action should not be construed as limiting
the scope of the invention inasmuch as the invention may be
practiced without such information.
[0142] The term "significantly," or "significant," is descriptive
of the changes in an identified property that occur in noticeable
or measurable amounts or increments, or where such changes would
have a noticeable, measurable, or unacceptable impact, e.g., a
detrimental impact. As such, the language "significantly reduce or
prevent gastrointestinal intolerance" includes a noticeable or
measurable reduction or prevention of gastrointestinal intolerance,
i.e., as opposed to the situation where the reduction or prevention
is not noticeable or measurable. For example, the number of
incidents of nausea, vomiting, and gastrointestinal-associa- ted
pain or irritation tracked over time may be used as a measure of
the impact of the therapeutic formulations of the present invention
on the reduction or prevention of gastrointestinal intolerance.
Additionally, the language "do not significantly affect the ability
of the therapeutic formulation" is descriptive of items that affect
the ability of the therapeutic formulation, but do not affect the
ability in an unacceptable manner to the extent that the cost
outweighs the benefit, and therefore do not "significantly affect"
the ability of the therapeutic formulation.
[0143] "Modulation of amyloid deposition" includes both inhibition,
as defined above, and enhancement of amyloid deposition or fibril
formation. The term "modulating" is intended, therefore, to
encompass 1) prevention or stopping of amyloid formation or
accumulation, inhibition or slowing down of further amyloid
aggregation in a subject with ongoing amyloidosis, e.g., already
having amyloid aggregates, and reducing or reversing of amyloid
aggregates in a subject with ongoing amyloidosis, and 2) enhancing
amyloid deposition, e.g., increasing the rate or amount of amyloid
deposition in vivo or in vitro. Amyloid-enhancing compounds may be
useful in animal models of amyloidosis, for example, to make
possible the development of amyloid deposits in animals in a
shorter period of time or to increase amyloid deposits over a
selected period of time. Amyloid-enhancing compounds may be useful
in screening assays for compounds which inhibit amyloidosis in
vivo, for example, in animal models, cellular assays and in vitro
assays for amyloidosis. Such compounds may be used, for example, to
provide faster or more sensitive assays for compounds. Modulation
of amyloid aggregation is determined relative to an untreated
subject or relative to the treated subject prior to treatment.
[0144] The term "therapeutic formulation" includes formulations
that perform their intended therapeutic function, e.g., prevent,
treat or inhibit amyloidosis, and are used to reduce or prevent
gastrointestinal intolerance (i.e. nausea and vomiting). The
reduction or prevention of gastrointestinal intolerance may, for
example, depend on direct physical interaction in the stomach or
indirect central action on the Central Nervous System.
[0145] In certain embodiments, the reduction or prevention of the
gastrointestinal intolerance is at least dependent upon the
therapeutic compound administered to the subject. In one
embodiment, the therapeutic compound having a desirable therapeutic
function is selected for inclusion in the therapeutic formulation
based on its ability to reduce or prevent gastrointestinal
intolerance. In certain embodiments, the compound is modified in
order to produce a therapeutic compound having a desirable
therapeutic function and an ability to reduce or prevent
gastrointestinal intolerance. For example, the compound may be
structurally modified (e.g., adding appropriate substituents or
altering the pharmaceutically acceptable counter ion) or
reformulated such that the compound has a desirable therapeutic
function and an ability to reduce or prevent gastrointestinal
intolerance.
[0146] In certain other embodiments, the reduction or prevention of
the gastrointestinal intolerance is not dependent upon the
therapeutic compound administered to the subject alone. For
example, in one embodiment, the reduction or prevention of the
gastrointestinal intolerance is not dependent upon the therapeutic
compound having the formula 3-amino-1-propanesulfonate/X, where X
is a counter cation or forms an ester with the sulfonate, e.g.,
3-amino-1-propanesulfonic acid, or the sodium salt thereof. In a
particular embodiment of the invention, the reduction or prevention
of the gastrointestinal intolerance is dependent on an additional
agent, such as enteric-coating or a modified-release agent.
[0147] In another embodiment, at least one additional agent is
included in the therapeutic formulation, where the additional agent
differs from the therapeutic compound. In a specific embodiment,
the additional agent imparts at least one desirable property to the
therapeutic formulation. In a particular embodiment, the desirable
property, at least in part, reduces or prevents gastrointestinal
intolerance. Accordingly, in an additional embodiment, an
additional agent may be used in the therapeutic formulation to
reduce or prevent gastrointestinal intolerance independently or in
conjunction with other methods of reducing or preventing
intolerance. For example, to protect against any possible
gastrointestinal intolerance that could result from the therapeutic
formulation, the tablets may be enteric-coated or a
modified-release agent may be added to control any rapid release of
the therapeutic compound in the stomach or intestine.
[0148] In one embodiment of the invention, the reduction or
prevention of gastrointestinal intolerance is accomplished by the
reduction or prevention of a local irritation as a result of high
pH generated during the dissolution of therapeutic compound in the
stomach subsequent to the administration of the therapeutic
compound. As an additional advantage of the therapeutic
formulations of the present invention, the reduction in
gastrointestinal intolerance also leads to improved compliance by
subjects of administration, e.g., patients.
[0149] In another particular embodiment, the therapeutic compound
of the invention is an alkylsulfonic acid. The term "alkylsulfonic
acid" includes substituted or unsubstituted alkylsulfonic acids,
and substituted or unsubstituted lower alkylsulfonic acids.
Amino-substituted compounds are especially noteworthy and the
invention pertains to substituted- or
unsubstituted-amino-substituted alkylsulfonic acids, and
substituted- or unsubstituted-amino-substituted lower alkylsulfonic
acids, an example of which is 3-amino-1-propanesulfonic acid. Also,
it should be noted that the term "alkylsulfonic acid" as used
herein is to be interpreted as being synonymous with the term
"alkanesulfonic acid."
[0150] In certain embodiments, the invention pertains to a
substituted or unsubstituted alkylsulfonic acid, substituted or
unsubstituted alkylsulfuric acid, substituted or unsubstituted
alkylthiosulfonic acid, substituted or unsubstituted
alkylthiosulfuric acid, or an ester or amide thereof, including
pharmaceutically acceptable salts thereof. For example, the
invention relates to a compound that is a substituted or
unsubstituted alkylsulfonic acid, or an ester or amide thereof,
including pharmaceutically acceptable salts thereof. In another
embodiment, the invention pertains to a compound that is a
substituted or unsubstituted lower alkylsulfonic acid, or an ester
or amide thereof, including pharmaceutically acceptable salts
thereof. Similarly, the invention includes a compound that is a
(substituted- or unsubstituted-amino)-subst- ituted alkylsulfonic
acid, or an ester or amide thereof, including pharmaceutically
acceptable salts thereof. In yet another embodiment, the compound
is a (substituted- or unsubstituted-amino)-substituted lower
alkylsulfonic acid, or an ester or amide thereof, including
pharmaceutically acceptable salts thereof.
[0151] Compositions of alkylsulfonic acids, including, for example,
3-amino-1-propanesulfonic acid and certain salts thereof have been
shown to be useful in the treatment of amyloid-.beta. related
diseases, including Alzheimer's disease and cerebral amyloid
angiopathy. See WO 96/28187, WO 01/85093, and U.S. Pat. No.
5,840,294.
[0152] One group of example alkylsulfonic acids have the following
structure 1
[0153] where Y is either an amino group (having the formula
--NR.sup.aR.sup.b wherein R.sup.a and R.sup.b are each
independently hydrogen, alkyl, aryl, or heterocyclyl, or R.sup.a
and R.sup.b, taken together with the nitrogen atom to which they
are attached, form a cyclic moiety having from 3 to 8 atoms in the
ring) or a sulfonic acid group (having the formula
--SO.sub.3.sup.-X.sup.+), n is an integer from 1 to 5, and X is
hydrogen or a cationic group (e.g., sodium). Some exemplary
alkylsulfonic acids include the following 2
[0154] In some cases, the alkylsulfonic acid is a "small molecule,"
that is, a compound that that is not itself the product of gene
transcription or translation (e.g., protein, RNA, or DNA) and has a
low molecular weight, e.g., less than about 2500. In other cases,
the compound may be a biological product, such as an antibody or an
immunogenic peptide.
[0155] Alkylsulfonic acids may be prepared by the methods
illustrated in the general reaction schemes as, for example,
described in U.S. Pat. Nos. 5,643,562; 5,972,328; 5,728,375;
5,840,294; 4,657,704; and the U.S. provisional patent application
No. 60/482,058, filed Jun. 23, 2003, identified by Attorney Docket
No. NBI-156-1, U.S. provisional patent application No. 60/512,135,
filed Oct. 17, 2003, identified by Attorney Docket No. NBI-156-2,
both entitled Synthetic Process for Preparing Compounds for
Treating Amyloidosis, and U.S. application Ser. No. ______, filed
Jun. 18, 2004, identified by Attorney Docket No. NBI-156, entitled
Improved Pharmaceutical Drug Candidates and Method for Preparation
Thereof, the contents of which are hereby expressly incorporated by
reference in their entireties, or by modifications thereof, using
readily available starting materials, reagents and conventional
synthesis procedures. In these reactions, it is also possible to
make use of variants which are in themselves known, but are not
mentioned. For example, functional and structural equivalents of
the compounds described herein and which have the same general
properties, (wherein one or more simple variations of substituents
are made that do not adversely affect the essential nature or the
utility of the compound) may be prepared according to a variety of
methods known in the art.
[0156] In general, the compounds of the present invention may be
prepared by the methods illustrated in the general reaction schemes
as, for example, described below, or by modifications thereof,
e.g., using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are in themselves known, but
are not mentioned here. Functional and structural equivalents of
the agents described herein and that have the same general
properties, wherein one or more simple variations of substituents
are made which do not adversely affect the essential nature or the
utility of the compound. The agents of the present invention may be
readily prepared in accordance with the synthesis schemes and
protocols described herein, as illustrated in the specific
procedures provided. However, those skilled in the art will
recognize that other synthetic pathways for forming the agents of
this invention may be used, and that the following is provided
merely by way of example, and is not limiting to the present
invention. See, e.g., "Comprehensive Organic Transformations" by R.
Larock, VCH Publishers (1989). It will be further recognized that
various protecting and deprotecting strategies will be employed
that are standard in the art (See, e.g., "Protective Groups in
Organic Synthesis" by Greene and Wuts). Those skilled in the
relevant arts will recognize that the selection of any particular
protecting group (e.g., amine and carboxyl protecting groups) will
depend on the stability of the protected moiety with regards to the
subsequent reaction conditions and will understand the appropriate
selections. Further illustrating the knowledge of those skilled in
the art is the following sampling of the extensive chemical
literature: "Chemistry of the Amino Acids" by J. P. Greenstein and
M. Winitz, John Wiley & Sons, Inc., New York (1961);
"Comprehensive Organic Transformations" by R. Larock, VCH
Publishers (1989); T. D. Ocain, et al., J. Med. Chem. 31, 2193-99
(1988); E. M. Gordon, et al., J. Med. Chem. 31, 2199-10 (1988);
"Practice of Peptide Synthesis" by M. Bodansky and A. Bodanszky,
Springer-Verlag, New York (1984); "Protective Groups in Organic
Synthesis" by T. Greene and P. Wuts (1991); "Asymmetric Synthesis:
Construction of Chiral Molecules Using Amino Acids" by G. M.
Coppola and H. F. Schuster, John Wiley & Sons, Inc., New York
(1987); "The Chemical Synthesis of Peptides" by J. Jones, Oxford
University Press, New York (1991); and "Introduction of Peptide
Chemistry" by P. D. Bailey, John Wiley & Sons, Inc., New York
(1992).
[0157] The chemical structures herein are drawn according to the
conventional standards known in the art. Thus, where an atom, such
as a carbon atom, as drawn appears to have an unsatisfied valency,
then that valency is assumed to be satisfied by a hydrogen atom
even though that hydrogen atom is not necessarily explicitly drawn.
The structures of some of the compounds of this invention include
stereogenic carbon atoms. It is to be understood that isomers
arising from such asymmetry (e.g., all enantiomers and
diastereomers) are included within the scope of this invention
unless indicated otherwise. That is, unless otherwise stipulated,
any chiral carbon center may be of either (R)- or
(S)-stereochemistry. Such isomers can be obtained in substantially
pure form by classical separation techniques and by
stereochemically-controlle- d synthesis. Furthermore, alkenes can
include either the E- or Z-geometry, where appropriate. In
addition, the compounds of the present invention may exist in
unsolvated as well as solvated forms with acceptable solvents such
as water, THF, ethanol, and the like, as well as polymorphic forms,
e.g., including pseudopolymorphic forms. The term "solvate"
represents an aggregate that comprises one or more molecules of a
compound, with one or more molecules of a pharmaceutical solvent,
such as water, ethanol, and the like.
[0158] Further examples of compounds that may be used as a compound
according to the present invention include those described in the
U.S. provisional patent application No. 60/480,906, filed Jun. 23,
2003, identified by Attorney Docket No. NBI-162-1, and U.S.
provisional patent application No. 60/512,047, filed Oct. 17, 2003,
identified by Attorney Docket No. NBI-162-2, U.S. application Ser.
No. ______, filed Jun. 18, 2004, identified by Attorney Docket No.
NBI-162A and U.S. application Ser. No. ______, filed Jun. 18, 2004,
identified by Attorney Docket No. NBI-162B, all entitled Methods
and Compositions for Treating Amyloid-Related Diseases; and U.S.
provisional patent application No. 60/480,928, also filed 23 Jun.
2003, identified by Attorney Docket No. NBI-163-1, U.S. provisional
patent application No. 60/512,018, filed Oct. 17, 2003, identified
by Attorney Docket No. NBI-163-2 and U.S. application Ser. No.
______, filed Jun. 18, 2004, identified by Attorney Docket No.
NBI-163, all entitled Methods and Compositions for the Treatment of
Amyloid- and Epileptogenesis-Associated Diseases.
[0159] In an embodiment, the invention pertains, at least in part
to a composition having a therapeutic compound that is a compound
of Formula I-A: 3
[0160] wherein:
[0161] R.sup.1 is a substituted or unsubstituted cycloalkyl, aryl,
arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic
fused ring group, or a substituted or unsubstituted
C.sub.2-C.sub.10 alkyl group;
[0162] R.sup.2 is selected from the group consisting of hydrogen,
alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and
benzoimidazolyl;
[0163] Y is SO.sub.3.sup.-X.sup.+, OSO.sub.3.sup.-X.sup.+, or
SSO.sub.3.sup.-X.sup.+;
[0164] X.sup.+ is hydrogen, a cationic group, or an ester forming
group (i.e., as in a prodrug,); and
[0165] each of L.sup.1 and L.sup.2 is independently a substituted
or unsubstituted C.sub.1-C.sub.5 alkyl group or absent, or a
pharmaceutically acceptable salt thereof, provided that when
R.sup.1 is alkyl, L.sup.1 is absent.
[0166] In another embodiment, the invention pertains, at least in
part to a composition having a therapeutic compound that is a
compound of Formula II-A: 4
[0167] wherein:
[0168] R.sup.1 is a substituted or unsubstituted cyclic, bicyclic,
tricyclic, or benzoheterocyclic group or a substituted or
unsubstituted C.sub.2-C.sub.10 alkyl group;
[0169] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, benzoimidazolyl, or linked to R.sup.1 to form a
heterocycle;
[0170] Y is SO.sub.3.sup.-X.sup.+, OSO.sub.3.sup.-X.sup.+, or
SSO.sub.3.sup.-X.sup.+;
[0171] X.sup.+ is hydrogen, a cationic group, or an ester forming
moiety;
[0172] m is 0 or 1;
[0173] n is 1, 2, 3, or 4;
[0174] L is substituted or unsubstituted C.sub.1-C.sub.3 alkyl
group or absent,
[0175] or a pharmaceutically acceptable salt thereof, provided that
when R.sup.1 is alkyl, L is absent. In a particular embodiment, n
is 3 or 4.
[0176] In yet another embodiment, the invention pertains, at least
in part to a composition having a therapeutic compound that is a
compound of Formula III-A: 5
[0177] wherein:
[0178] A is nitrogen or oxygen;
[0179] R.sup.11 is hydrogen, salt-forming cation, ester forming
group, --(CH.sub.2).sub.x-Q, or when A is nitrogen, A and R.sup.11
taken together may be a natural or unnatural amino acid residue or
a salt or ester thereof;
[0180] Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or benzoimidazolyl;
[0181] x is 0, 1, 2, 3, or 4;
[0182] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
[0183] R.sup.3, R.sup.3a, R.sup.4, R.sup.4a, R.sup.5, R.sup.5a,
R.sup.6, R.sup.6a, R.sup.7 and R.sup.7a are each independently
hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino,
tetrazolyl, or two R groups on adjacent ring atoms taken together
with the ring atoms form a double bond. In a particular embodiment,
n is 3 or 4. In certain embodiments, one of R.sup.3, R.sup.3a,
R.sup.4, R.sup.4a, R.sup.5, R.sup.5a, R.sup.6, R.sup.6a, R.sup.7
and R.sup.7a is a moiety of Formula IIIa-A: 6
[0184] wherein:
[0185] m is 0, 1, 2, 3, or 4;
[0186] R.sup.A, R.sup.B, R.sup.C, R.sup.D, and R.sup.E are
independently selected from a group of hydrogen, halogen, hydroxyl,
alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl,
tetrazolyl, benzothiazolyl, and benzoimidazolyl; and
pharmaceutically acceptable salts and esters thereof. In certain
embodiments, said compound is not 3-(4-phenyl-1, 2, 3,
6-tetrahydro-1-pyridyl)-1-propanesulfonic acid.
[0187] An ester forming group or moiety includes groups, which when
bound, form an ester. Examples of such groups include substituted
or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
Particular examples of possible esters include methyl, ethyl, and
t-butyl. Additionally, examples of salt forming cations include
pharmaceutically acceptable salts described herein as well as
lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron,
and ammonium. In a further embodiment, the salt forming cation is a
sodium salt.
[0188] In yet another embodiment, the invention pertains at least
in part to a composition having a therapeutic compound that is a
compound of Formula IV: 7
[0189] wherein:
[0190] A is nitrogen or oxygen;
[0191] R.sup.11 is hydrogen, salt-forming cation, ester forming
group, --(CH.sub.2).sub.x-Q or when A is nitrogen, A and R.sup.11
taken together may be a natural or unnatural amino acid residue or
a salt or ester thereof;
[0192] Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or benzoimidazolyl;
[0193] x is 0, 1, 2, 3, or 4;
[0194] n is 0, 1, 2 , 3, 4, 5, 6, 7, 8, 9, or 10;
[0195] R.sup.4, R.sup.4a, R.sup.5, R.sup.5a, R.sup.6, R.sup.6a,
R.sup.7, and R.sup.7a are each independently hydrogen, alkyl,
mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl,
R.sup.4 and R.sup.5 taken together, with the ring atoms they are
attached to, form a double bond, or R.sup.6 and R.sup.7 taken
together, with the ring atoms they are attached to, form a double
bond;
[0196] m is 0, 1, 2, 3, or 4;
[0197] R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
independently selected from a group of hydrogen, halogen, hydroxyl,
alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl,
tetrazolyl, benzothiazolyl, and benzoimidazolyl, and
pharmaceutically acceptable salts and esters thereof. In a
particular embodiment, n is 3 or 4.
[0198] In another embodiment, the invention includes a composition
having a therapeutic compound that is a compound of Formula V-A:
8
[0199] wherein:
[0200] A is nitrogen or oxygen;
[0201] R.sup.11 is hydrogen, salt-forming cation, ester forming
group, --(CH.sub.2).sub.x-Q, or when A is nitrogen, A and R.sup.11
taken together may be a natural or unnatural amino acid residue or
a salt or ester thereof;
[0202] Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or benzoimidazolyl;
[0203] x is 0, 1, 2, 3, or 4;
[0204] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
[0205] aa is a natural or unnatural amino acid residue;
[0206] m is 0, 1, 2, or 3;
[0207] R.sup.14 is hydrogen or protecting group;
[0208] R.sup.15 is hydrogen, alkyl or aryl, and pharmaceutically
acceptable salts and prodrugs thereof. In a particular embodiment,
n is 3 or 4.
[0209] In another embodiment, the invention includes a composition
having a therapeutic compound that is a compound of the Formula
VI-A: 9
[0210] wherein:
[0211] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
[0212] A is oxygen or nitrogen;
[0213] R.sup.11 is hydrogen, salt-forming cation, ester forming
group, --(CH.sub.2).sub.x-Q, or when A is nitrogen, A and R.sup.11
taken together may be a natural or unnatural amino acid residue or
a salt or ester thereof;
[0214] Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or benzoimidazolyl;
[0215] x is 0, 1, 2, 3, or 4;
[0216] R.sup.19 is hydrogen, alkyl or aryl;
[0217] Y.sup.1 is oxygen, sulfur, or nitrogen;
[0218] Y.sup.2 is carbon, nitrogen, or oxygen;
[0219] R.sup.20 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl,
tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
[0220] R.sup.21 is hydrogen, alkyl, mercaptoalkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl,
tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent
if Y.sup.2 is oxygen;
[0221] R.sup.22 is hydrogen, alkyl, mercaptoalkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl,
tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or
R.sup.22 is hydrogen, hydroxyl, alkoxy or aryloxy if Y.sup.1 is
nitrogen; or R.sup.22 is absent if Y.sup.1 is oxygen or sulfur; or
R.sup.22 and R.sup.21 may be linked to form a cyclic moiety if
Y.sup.1 is nitrogen;
[0222] or pharmaceutically acceptable salts thereof. In a
particular embodiment, n is 3 or 4.
[0223] In another embodiment, the invention includes a composition
having a therapeutic compound that is a compound of Formula VII-A:
10
[0224] wherein:
[0225] n is 2, 3, or 4;
[0226] A is oxygen or nitrogen;
[0227] R.sup.11 is hydrogen, salt-forming cation, ester forming
group, --(CH.sub.2).sub.x-Q, or when A is nitrogen, A and R.sup.11
taken together may be a natural or unnatural amino acid residue or
a salt or ester thereof;
[0228] Q is hydrogen, thiazolyl, triazolyl, imidazolyl,
benzothiazolyl, or benzoimidazolyl;
[0229] x is 0, 1, 2, 3, or 4;
[0230] G is a direct bond or oxygen, nitrogen, or sulfur;
[0231] z is 0, 1, 2, 3, 4, or 5;
[0232] m is 0 or 1;
[0233] R.sup.24 is selected from the group consisting of hydrogen,
alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl,
aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl,
triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
[0234] each R.sup.25 is independently selected from hydrogen,
halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl,
carbocyclic, or heterocyclic, and pharmaceutically acceptable salts
thereof. In a particular embodiment, n is 3 or 4.
[0235] Additional compounds include, for example, therapeutic
compounds of Formula (I-B): 11
[0236] wherein:
[0237] X is oxygen or nitrogen;
[0238] Z is C.dbd.O, S(O).sub.2, or P(O)OR.sup.7;
[0239] m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10;
[0240] R.sup.1 and R.sup.7 are each independently hydrogen, metal
ion, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, a
moiety together with X to form a natural or unnatural amino acid
residue, or --(CH.sub.2).sub.p--Y;
[0241] Y is hydrogen or a heterocyclic moiety selected from the
group consisting of thiazolyl, triazolyl, tetrazolyl, imidazolyl,
benzothiazolyl, and benzoimidazolyl;
[0242] p is 0, 1, 2, 3, or 4;
[0243] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or
alkoxycarbonyl;
[0244] R.sup.3 is hydrogen, amino, cyano, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclic, sunbstituted or
unsubstituted aryl, heteroaryl, thiazolyl, triazolyl, tetrazolyl,
imidazolyl, benzothiazolyl, or benzoimidazolyl, and
pharmaceutically acceptable salts, esters, and prodrugs
thereof.
[0245] In a further embodiment, m is 0, 1, or 2. In another further
embodiment, n is 0, 1, or 2, e.g., 1 or 2. In another further
embodiment, R.sup.3 is aryl, e.g., heteroaryl or phenyl. In yet
another embodiment, Z is S(O).sub.2.
[0246] In another embodiment, the therapeutic compound of the
invention is of the Formula (II-B) 12
[0247] wherein:
[0248] X is oxygen or nitrogen;
[0249] m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10;
[0250] R.sup.1 is hydrogen, metal ion, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, or a moiety together with X to
form a natural or unnatural amino acid residue, or
--(CH.sub.2).sub.p--Y;
[0251] Y is hydrogen or a heterocyclic moiety selected from the
group consisting of thiazolyl, triazolyl, tetrazolyl, imidazolyl,
benzothiazolyl, and benzoimidazolyl;
[0252] each R.sup.4 is independently selected from the group
consisting of hydrogen, halogen, hydroxyl, thiol, amino, cyano,
nitro, alkyl, aryl, carbocyclic or heterocyclic;
[0253] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or
alkoxycarbonyl;
[0254] J is absent, oxygen, nitrogen, sulfur, or a divalent
link-moiety consisting of, without limitation to, lower alkylene,
alkylenyloxy, alkylenylamino, alkylenylthio, alkylenyloxyalkyl,
alkylenylamonialkyl, alkylenylthioalkyl, alkenyl, alkenyloxy,
alkenylamino, or alkenylthio; and
[0255] q is 1, 2, 3, 4, or 5, and pharmaceutically acceptable
salts, esters and prodrugs thereof. In a particular embodiment, n
is 1 or 2.
[0256] In a yet further embodiment, the therapeutic compound of the
invention is of the Formula (III-B): 13
[0257] wherein:
[0258] X is oxygen or nitrogen;
[0259] m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10;
[0260] q is 1, 2, 3, 4, or 5;
[0261] R.sup.1 is hydrogen, metal ion, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, or a moiety together with X to
form a natural or unnatural amino acid residue, or
--(CH.sub.2).sub.p--Y;
[0262] Y is hydrogen or a heterocyclic moiety selected from the
group consisting of thiazolyl, triazolyl, tetrazolyl, imidazolyl,
benzothiazolyl, and benzoimidazolyl;
[0263] p is 0, 1, 2, 3, or 4;
[0264] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or
alkoxycarbonyl;
[0265] R.sup.5 is selected from the group consisting of hydrogen,
halogen, amino, nitro, hydroxy, carbonyl, thiol, carboxy, alkyl,
alkoxy, alkoxycarbonyl, acyl, alkylamino, and acylamino;
[0266] J is absent, oxygen, nitrogen, sulfur, or a divalent
link-moiety consisting of, without limitation to, lower alkylene,
alkylenyloxy, alkylenylamino, alkylenylthio, alkylenyloxyalkyl,
alkylenylamonialkyl, alkylenylthioalkyl, alkenyl, alkenyloxy,
alkenylamino, or alkenylthio; and
[0267] pharmaceutically acceptable salts, esters, and prodrugs
thereof. In a particular embodiment, n is 1 or 2.
[0268] In yet another embodiment, the therapeutic compound of the
invention is: 14
[0269] wherein:
[0270] X is oxygen or nitrogen;
[0271] m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10;
[0272] q is 1, 2, 3, 4, or 5;
[0273] R.sup.1 is hydrogen, metal ion, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, or a moiety together with X to
form a natural or unnatural amino acid residue, or
--(CH.sub.2).sub.p--Y;
[0274] Y is hydrogen or a heterocyclic moiety selected from the
group consisting of thiazolyl, triazolyl, tetrazolyl, imidazolyl,
benzothiazolyl, and benzoimidazolyl;
[0275] p is 0, 1, 2, 3, or 4;
[0276] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or
alkoxycarbonyl;
[0277] R.sup.5 is selected from the group consisting of hydrogen,
halogen, amino, nitro, hydroxy, carbonyl, thiol, carboxy, alkyl,
alkoxy, alkoxycarbonyl, acyl, alkylamino, acylamino; and
[0278] pharmaceutically acceptable salts, esters, and prodrugs
thereof. In a further embodiment, m is 0. In a particular
embodiment, n is 1 or 2.
[0279] In another embodiment, the invention pertains to therapeutic
compounds of Formula (V-B): 15
[0280] wherein:
[0281] Z is C.dbd.O, S(O).sub.2, or P(O)OR.sup.7;
[0282] R.sup.1 is hydrogen, metal ion, alkyl, mercaptoalkyl,
alkenyl, alkynyl, cycloalkyl, aryl, or a moiety together with X to
form a natural or unnatural amino acid residue, or
--(CH.sub.2).sub.p--Y;
[0283] Y is hydrogen or a heterocyclic moiety selected from the
group consisting of thiazolyl, triazolyl, tetrazolyl, imidazolyl,
benzothiazolyl, and benzoimidazolyl;
[0284] m and n are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10;
[0285] R.sup.2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
and
[0286] R.sup.6 is a substituted or unsubstituted heterocyclic
moiety. In a further embodiment, m is 0 or 1. In another
embodiment, n is 0 or 1. In another further embodiment, R.sup.6 is
thiazolyl, oxazoylyl, pyrazolyl, indolyl, pyridinyl, thiazinyl,
thiophenyl, benzothiophenyl, dihydroimidazolyl, dihydrothiazolyl,
oxazolidinyl, thiazolidinyl, tetrahydropyrimidinyl, or oxazinyl. In
yet another embodiment, Z is S(O).sub.2. In a particular
embodiment, n is 1 or 2.
[0287] In certain embodiments of the invention, the therapeutic
formulations of the invention may contain pharmaceutically
acceptable inactive ingredients and a therapeutic compound having
the formula 3-amino-1-propanesulfonate/X, where X is a counter
cation or forms an ester with the sulfonate, wherein the ester or
counter cation includes alcohol radicals or positively charged
atoms and moieties, respectively, that do not significantly affect
the ability of the therapeutic formulation to reduce or prevent
gastrointestinal intolerance. In a preferred embodiment, the
cationic group is hydrogen (H.sup.+) and the compound is
3-amino-1-propanesulfonic acid. In certain other embodiments, the
hydrogen is replaced by a pharmaceutically acceptable cation or an
alcohol radical or its equivalent, and the compound is a salt or
ester of the acid. Pharmaceutically acceptable salts or esters of
the therapeutic compound that do not significantly affect the
ability of the therapeutic formulation to reduce or prevent
gastrointestinal intolerance are within the scope of the invention.
For example, the cation can be a pharmaceutically acceptable alkali
metal, alkaline earth, higher valency cation (e.g., aluminum salt),
polycationic counter ion or ammonium, and the alcohol radical can
be a pharmaceutically acceptable alcohol radical. In a particular
embodiment, the pharmaceutically acceptable salt is a sodium salt,
however, other salts are also contemplated within their
pharmaceutically acceptable range.
[0288] In general, the therapeutic compounds appropriate for use in
the therapeutic formulations of the invention comprise at least one
sulfonate group covalently bonded to a substituted or unsubstituted
aromatic or aliphatic group.
[0289] In another embodiment, the therapeutic compound has at least
one sulfonate group covalently bonded to a substituted or
unsubstituted aliphatic group. In a similar embodiment the
therapeutic compound has at least two sulfonate groups covalently
bonded to a substituted or unsubstituted aliphatic group. In
another embodiment, the therapeutic compound has at least one
sulfonate group covalently bonded to a substituted or unsubstituted
lower alkyl group. In a similar embodiment the therapeutic compound
has at least two sulfonate groups covalently bonded to a
substituted or unsubstituted lower alkyl group.
[0290] In yet another embodiment, the therapeutic compound has at
least one sulfonate group covalently bonded to an amino-substituted
aliphatic group. In a similar embodiment the therapeutic compound
has at least two sulfonate groups covalently bonded to an
amino-substituted aliphatic group. In still yet another embodiment,
the therapeutic compound has at least one sulfonate group
covalently bonded to an amino-substituted lower alkyl group. In a
similar embodiment the therapeutic compound has at least two
sulfonate groups covalently bonded to an amino-substituted lower
alkyl group.
[0291] A "sulfonate group" as used herein is an --SO.sub.3.sup.-H
or --SO.sub.3X group bonded to a carbon atom, where X is a cationic
group or an ester group. Similarly, a "sulfonic acid" compound has
a --SO.sub.3H group bonded to a carbon atom. A "sulfate" as used
herein is an --OSO.sub.3.sup.-H or --OSO.sub.3X group bonded to a
carbon atom, where X is a cationic group or an ester group; and a
"sulfuric acid" compound has a --OSO.sub.3H group bonded to a
carbon atom. According to the invention, a suitable cationic group
may be a hydrogen atom. In certain cases, the cationic group may
actually be another group on the therapeutic compound that is
positively charged at physiological pH, for example an amino group.
Such compounds containing such a cationic group covalently bonded
to the therapeutic compound itself may be referred to as an "inner
salt" or "zwitterion." For example, the compound
3-amino-1-propanesulfonic acid may form an inner salt or zwitterion
under appropriate conditions.
[0292] Unless otherwise stipulated, the chemical moieties herein
may be substituted or unsubstituted. In some embodiments, the term
"substituted" means that the moiety has substituents placed on the
moiety other than hydrogen which allow the molecule to perform its
intended function. Examples of substituents, which are not intended
to be limiting, include moieties selected from straight or branched
alkyl (preferably C.sub.1-C.sub.5), cycloalkyl (preferably
C.sub.3-C.sub.8), alkoxy (preferably C.sub.1-C.sub.6), thioalkyl
(preferably C.sub.1-C.sub.6), alkenyl (preferably C.sub.2-C.sub.6),
alkynyl (preferably C.sub.2-C.sub.6), heterocyclic, carbocyclic,
aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g.,
benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl,
alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other
such acyl group, heteroarylcarbonyl, or heteroaryl group,
(CR'R").sub.0-3NR'R" (e.g., --NH.sub.2), (CR'R").sub.0-3CN (e.g.,
--CN), --NO.sub.2, halogen (e.g., --F, --Cl, --Br, or --I),
(CR'R").sub.0-3C(halogen).sub.3 (e.g., --CF.sub.3),
(CR'R").sub.0-3CH(halogen).sub.2, (CR'R").sub.0-3CH.sub.2(halogen),
(CR'R").sub.0-3CONR'R", (CR'R").sub.0-3(CNH)NR'R",
(CR'R").sub.0-3S(O).sub.1-2NR'R", (CR'R").sub.0-3CHO,
(CR'R").sub.0-3O(CR'R").sub.0-3H, (CR'R").sub.0-3S(O).sub.0-3R'
(e.g., --SO.sub.3H, --OSO.sub.3H), (CR'R").sub.0-3O(CR'R").sub.0-3H
(e.g., --CH.sub.2OCH.sub.3 and --OCH.sub.3),
(CR'R").sub.0-3S(CR'R").sub.0-3H (e.g., --SH and --SCH.sub.3),
(CR'R").sub.0-3OH (e.g., --OH), (CR'R").sub.0-3COR',
(CR'R").sub.0-3(substituted or unsubstituted phenyl),
(CR'R").sub.0-3(C.sub.3-C.sub.8 cycloalkyl),
(CR'R").sub.0-3CO.sub.2R' (e.g., --CO.sub.2H), or
(CR'R").sub.0-3OR' group, or the side chain of any naturally
occurring amino acid; wherein R' and R" are each independently
hydrogen, a C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl,
C.sub.2-C.sub.5 alkynyl, or aryl group. "Substituents" may also
include, for example, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate,
sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido,
heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
[0293] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" includes all permissible
substituents of organic compounds. In a broad aspect, the
permissible substituents include acyclic and cyclic, branched and
unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
substituents of organic compounds. The permissible substituents can
be one or more and the same or different for appropriate organic
compounds.
[0294] In certain embodiments, a "substituent" may be selected from
the group consisting of, for example, halogeno, trifluoromethyl,
nitro, cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkylcarbonyloxy,
arylcarbonyloxy, C.sub.1-C.sub.6 alkoxycarbonyloxy,
aryloxycarbonyloxy, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
arylthio, heterocyclyl, aralkyl, and aryl (including heteroaryl)
groups.
[0295] In general, the therapeutic compounds of the invention are
small molecules. A "small molecule" refers to a compound that is
not itself the product of gene transcription or translation (e.g.,
protein, RNA, or DNA). Preferably a "small molecule" is a low
molecular weight compound, e.g., less than 7500 amu, more
preferably less 5000 amu and even more preferably less than 1000
amu.
[0296] The term "amine" or "amino," as used herein, refers to an
unsubstituted or substituted moiety of the formula
--NR.sup.aR.sup.b, in which R.sup.a and R.sup.b are each
independently hydrogen, alkyl, aryl, or heterocyclyl, or R.sup.a
and R.sup.b, taken together with the nitrogen atom to which they
are attached, form a cyclic moiety having from 3 to 8 atoms in the
ring. Thus, the term amino includes cyclic amino moieties such as
piperidinyl or pyrrolidinyl groups, unless otherwise stated. Thus,
the term "alkylamino" as used herein means an alkyl group having an
amino group attached thereto. Suitable alkylamino groups include
groups having 1 to about 12 carbon atoms, for example, 1 to about 6
carbon atoms. The term amino includes compounds or moieties in
which a nitrogen atom is covalently bonded to at least one carbon
or heteroatom. The term "dialkylamino" includes groups wherein the
nitrogen atom is bound to at least two alkyl groups. The term
"arylamino" and "diarylamino" include groups wherein the nitrogen
is bound to at least one or two aryl groups, respectively. The term
"alkylarylamino" refers to an amino group which is bound to at
least one alkyl group and at least one aryl group. The term
"alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group
substituted with an alkylamino group. The term "amide" or
"aminocarbonyl" includes compounds or moieties which contain a
nitrogen atom which is bound to the carbon of a carbonyl or a
thiocarbonyl group.
[0297] The term "aliphatic group" includes organic compounds
characterized by straight or branched chains, typically having
between 1 and 22 carbon atoms. Aliphatic groups include alkyl
groups, alkenyl groups and alkynyl groups. The chains may be
branched or cross-linked. Alkyl groups include saturated
hydrocarbons having one or more carbon atoms, including
straight-chain alkyl groups and branched-chain alkyl groups. The
term "alicyclic group" includes closed ring structures of three or
more carbon atoms. Alicyclic groups include cycloparaffins or
naphthenes that are saturated cyclic hydrocarbons, cycloolefins
which are unsaturated with two or more double bonds, and
cycloacetylenes which have a triple bond. They do not include
aromatic groups. Examples of cycloparaffins include cyclopropane,
cyclohexane, and cyclopentane. Examples of cycloolefins include
cyclopentadiene and cyclooctatetraene. Alicyclic groups also
include polycyclic rings, e.g., fused ring structures, and
substituted alicyclic groups such as alkyl substituted alicyclic
groups. "Polycyclyl" or "polycyclic group" includes two or more
cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls,
aryls or heterocyclyls) in which one or more carbons are common to
two adjoining rings, e.g., the rings are "fused rings" or
spiro-rings. Rings that are joined through non-adjacent atoms are
termed "bridged" rings.
[0298] As used herein, "alkyl" groups include saturated
hydrocarbons having one or more carbon atoms, including
straight-chain alkyl groups, e.g., methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.; cyclic alkyl
groups (or "cycloalkyl" or "alicyclic" or "carbocyclic" groups),
e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, etc.; branched-chain alkyl groups, e.g., isopropyl,
tert-butyl, sec-butyl, isobutyl, etc.; and alkyl-substituted alkyl
groups, e.g., alkyl-substituted cycloalkyl groups and
cycloalkyl-substituted alkyl groups.
[0299] Accordingly, the invention relates to, for example,
substituted or unsubstituted alkylsulfonic acids that are
substituted or unsubstituted straight-chain alkylsulfonic acids,
substituted or unsubstituted cycloalkylsulfonic acids, and
substituted or unsubstituted branched-chain alkylsulfonic
acids.
[0300] In certain embodiments, a straight-chain or branched-chain
alkyl group may have 30 or fewer carbon atoms in its backbone,
e.g., C.sub.1-C.sub.30 for straight-chain or C.sub.3-C.sub.30 for
branched-chain. In certain embodiments, a straight-chain or
branched-chain alkyl group may have 20 or fewer carbon atoms in its
backbone, e.g., C.sub.1-C.sub.20 for straight-chain or
C.sub.3-C.sub.20 for branched-chain, and more particularly, for
example, 18 or fewer. Additionally, example cycloalkyl groups have
from 4-10 carbon atoms in their ring structure, e.g., 4-7 carbon
atoms in the ring structure.
[0301] The term "lower alkyl" refers to alkyl groups having from 1
to 8 carbons in the chain, and to cycloalkyl groups having from 3
to 8 carbons in the ring structure. Unless the number of carbons is
otherwise specified, "lower" as in "lower alkyl," means that the
moiety has at least one and less than about 8 carbon atoms. In
certain embodiments, a straight-chain or branched-chain lower alkyl
group has 6 or fewer carbon atoms in its backbone (e.g.,
C.sub.1-C.sub.6 for straight-chain, C.sub.3-C.sub.6 for
branched-chain), for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, cycloalkyl
groups may have from 3-8 carbon atoms in their ring structure, for
example, 5 or 6 carbons in the ring structure. The term "C1-C6" as
in "C1-C6 alkyl" means alkyl groups containing 1 to 6 carbon
atoms.
[0302] Moreover, unless otherwise specified the term alkyl includes
both "unsubstituted alkyls" and "substituted alkyls," the latter of
which refers to alkyl groups having substituents replacing one or
more hydrogens on one or more carbons of the hydrocarbon backbone.
Such substituents may include, for example, alkenyl, alkynyl,
halogeno, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkylaryl, or aromatic (including heteroaromatic) groups.
[0303] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous to alkyls, including straight and
branched chains, and cyclical structures, but which contain at
least one double or triple bond respectively. Suitable alkenyl and
alkynyl groups include groups having 2 to about 12 carbon atoms,
preferably from 2 to about 6 carbon atoms.
[0304] The term "aromatic group" includes unsaturated cyclic
hydrocarbons containing one or more rings. In general, the term
"aryl" includes groups, including 5- and 6-membered single-ring
aromatic groups that may include from zero to four heteroatoms, for
example, groups derived from benzene, pyrrole, furan, thiophene,
thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole,
oxazole, isooxazole, pyridine, pyrazine, pyridazine, and
pyrimidine, and the like. Furthermore, the term aryl includes
multicyclic aryl groups, e.g., groups derived from tricyclic,
bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole,
benzothiazole, benzoimidazole, benzothiophene,
methylenedioxyphenyl, quinoline, isoquinoline, napthyridine,
indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
Those aryl groups having heteroatoms in the ring structure may also
be referred to as "aryl heterocycles," "heteroaryls," or
"heteroaromatics".
[0305] Aryl groups may also be fused or bridged with alicyclic or
heterocyclic rings which are not aromatic so as to form a polycycle
(e.g., tetralin). Those aryl groups having heteroatoms in the ring
structure may also be referred to as aryl heterocycles,
heterocycles, heteroaryls, or heteroaromatics, which, for example,
include any ring formed that incorporates a heteroatom or an atom
that is not carbon. The ring may be saturated or unsaturated and
may contain one or more double bonds. Examples of some heterocyclic
groups include pyridyl, furanyl, thiophenyl, morpholinyl, and
indolyl groups.
[0306] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus. Heterocyclic groups also include
closed ring structures in which one or more of the atoms in the
ring is an element other than carbon, for example, nitrogen,
sulfur, or oxygen. Heterocyclic groups may be saturated or
unsaturated and heterocyclic groups such as pyrrole and furan may
have aromatic character. They include fused ring structures such as
quinoline and isoquinoline. Other examples of heterocyclic groups
include pyridine and purine. Examples of heteroaromatic and
heteroalicyclic groups may have 1 to 3 separate or fused rings with
3 to about 8 members per ring and one or more N, O, or S atoms,
e.g., coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl,
pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl,
benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl,
piperidinyl, morpholino, and pyrrolidinyl.
[0307] III. Therapeutic Formulations of the Invention
[0308] The invention also relates to a pharmaceutical composition
for inhibiting amyloid deposition in a subject comprising a
therapeutic formulation as defined herein, in an amount sufficient
to inhibit amyloid deposition in a subject, and a pharmaceutically
acceptable vehicle.
[0309] In another embodiment, the invention is a pharmaceutical
composition for treating amyloidosis in a subject comprising a
therapeutic formulation as described herein, in an amount
sufficient to inhibit amyloid deposition in a subject, and a
pharmaceutically acceptable vehicle.
[0310] In another embodiment, the present invention pertains to a
pharmaceutical composition for treating or preventing an
amyloid-related disease, e.g., type II diabetes or A.beta.-related
disease, e.g., Alzheimer's disease, cerebral amyloid angiopathy,
inclusion body myositis, macular degeneration, Down's syndrome, and
hereditary cerebral hemorrhage, comprising a therapeutic
formulation comprising a therapeutic compound formulated to
significantly reduce or prevent gastrointestinal intolerance, in an
amount sufficient to prevent or treat an amyloid-related disease in
a subject, and a pharmaceutically acceptable vehicle.
[0311] In certain embodiments, the therapeutic compound of the
therapeutic formulations of the invention interacts with a binding
site for a basement membrane glycoprotein or proteoglycan in an
amyloidogenic protein and thereby inhibits the binding of the
amyloidogenic protein to the basement membrane constituent.
Basement membrane glycoproteins and proteoglycans include laminin,
collagen type IV, fibronectin, agrin, perlecan, and heparan sulfate
proteoglycan (HSPG). In a particular embodiment, the therapeutic
compound inhibits an interaction between an amyloidogenic protein
and agrin, perlecan, or HSPG. Furthermore, consensus binding site
motifs for HSPG in amyloidogenic proteins have been described (see
e.g. Cardin and Weintraub (1989) Arteriosclerosis 9: 21-32).
[0312] Accordingly, the invention includes a packaged
pharmaceutical composition for inhibiting amyloid deposition in a
subject, comprising a container holding a therapeutically effective
amount of a therapeutic formulation as described herein; and
instructions for using the compound for inhibiting amyloid
deposition in a subject. In certain embodiments, the disease
related to such amyloid deposition is selected from the group
consisting of Alzheimer's disease, cerebral amyloid angiopathy,
inclusion body myositis, macular degeneration, Down's syndrome,
Mild Cognitive Impairment, type II diabetes, and hereditary
cerebral hemorrhage.
[0313] The term "container" includes any receptacle for holding the
therapeutic formulation. For example, in one embodiment, the
container is the packaging that contains the formulation. In other
embodiments, the container is not the packaging that contains the
formulation, i.e., the container is a receptacle, such as a box or
vial that contains the packaged formulation or unpackaged
formulation and the instructions for use of the formulation.
Moreover, packaging techniques are well known in the art. It should
be understood that the instructions for use of the therapeutic
formulation may be contained on the packaging containing the
therapeutic formulation, and as such the instructions form an
increased functional relationship to the packaged product. However,
it should be understood that the instructions can contain
information pertaining to the compound's ability to perform its
intended function, e.g., reduce or prevent gastrointestinal
intolerance.
[0314] In another embodiment, the invention includes a packaged
pharmaceutical composition for treating amyloidosis in a subject,
comprising a container holding a therapeutically effective amount
of a therapeutic formulation as described herein; and instructions
for using the compound for treating amyloidosis in a subject.
[0315] In yet another embodiment, the invention includes a packaged
pharmaceutical composition for treating a viral infection,
comprising a container holding a therapeutically effective amount
of a therapeutic formulation as described herein; and instructions
for using the compound for treating the viral infection.
[0316] Another embodiment of the invention pertains to a packaged
pharmaceutical composition for treating a bacterial infection,
comprising a container holding a therapeutically effective amount
of a therapeutic formulation of the invention; and instructions for
using the therapeutic compound for treating the bacterial
infection.
[0317] Another embodiment of the invention pertains to a packaged
pharmaceutical composition for inhibiting the binding of a
chemokine to a glycosaminoglycan, comprising a container holding a
therapeutically effective amount of a therapeutic formulation of
the invention; and instructions for using the therapeutic compound
for inhibiting the binding of a chemokine to a
glycosaminoglycan.
[0318] The therapeutic formulations of the invention may also
include combinations of two or more therapeutic compounds.
Accordingly, the invention relates to a therapeutic formulation for
the treatment of Alzheimer's disease comprising
3-amino-1-propanesulfonic acid and a second drug that targets
additional symptoms, e.g., secondary symptoms of Alzheimer's
disease. In certain embodiments, the "second drug" may be a
cholinesterase inhibitor, such as an acetyl-cholinesterase or
butyryl-cholinesterase inhibitor, e.g., tacrine, donepezil,
rivastigmine, or galantamine. In another embodiment, the second
drug may be an NMDA receptor antagonist, such as memantine. In yet
another embodiment, the the second drug may be an antioxidant,
vitamin E, estrogen, a nonsteroidal anti-inflammatory agent (e.g.,
aspirin or naproxen), a cholesterol modifying agent such as statin,
or ginkgo biloba.
[0319] The therapeutic formulation of the invention may further
include a pharmaceutically acceptable vehicle. As used herein
"pharmaceutically acceptable vehicle" includes any and all
coatings, antibacterial and antifungal agents, and absorption
delaying agents, and the like that are compatible with the activity
of the compound, are physiologically acceptable to the subject, and
that do not significantly affect the ability of the therapeutic
formulation to perform its intended function or do not
significantly affect the ability of the therapeutic formulation to
reduce or prevent gastrointestinal intolerance. Supplementary
active compounds can also be incorporated into the compositions as
long as they do not significantly affect the ability of the
therapeutic formulation to reduce or prevent nausea.
[0320] Active compounds are administered at a therapeutically
effective dosage sufficient to inhibit amyloid deposition in a
subject. A "therapeutically effective dosage" preferably inhibits
amyloid deposition by at least about 20%, more preferably by at
least about 40%, even more preferably by at least about 60%, and
still more preferably by at least about 80% relative to untreated
subjects. The ability of a compound to inhibit amyloid deposition
can be evaluated in an animal model system that may be predictive
of efficacy in inhibiting amyloid deposition in human diseases.
Alternatively, the ability of a compound to inhibit amyloid
deposition can be evaluated by examining the ability of the
compound to inhibit an interaction between an amyloidogenic protein
and a basement membrane constituent, e.g., as described in U.S.
Pat. No. 5,164,295, which is hereby expressly incorporated herein
by reference, or by the mass spectroscopy assay described in
Example 5.
[0321] The term "subject" includes living organisms in which
amyloidosis can occur, or which are susceptible to amyloid
diseases, e.g., Alzheimer's disease, Down's syndrome, Mild
Cognitive Impairment, CAA, dialysis-related (.beta..sub.2M)
amyloidosis, secondary (AA) amyloidosis, primary (AL) amyloidosis,
hereditary amyloidosis, diabetes, etc. Examples of subjects include
humans, monkeys, cows, sheep, goats, dogs, and cats. The language
"subject" includes animals (e.g., mammals, e.g., cats, dogs,
horses, pigs, cows, goats, sheep, rodents, e.g., mice or rats,
rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys,
gorillas, and humans)), as well as chickens, ducks, peking ducks,
geese, and transgenic species thereof.
[0322] In certain embodiments of the invention, the subject is in
need of treatment by the methods of the invention, and is selected
for treatment based on this need. A subject in need of treatment is
art-recognized, and includes subjects that have been identified as
having a disease or disorder related to amyloid-deposition or
amyloidosis, having a symptom of such a disease or disorder, or at
risk of such a disease or disorder, and would be expected, based on
diagnosis, e.g., medical diagnosis, to benefit from treatment
(e.g., curing, healing, preventing, alleviating, relieving,
altering, remedying, ameliorating, improving, or affecting the
disease or disorder, the symptom of the disease or disorder, or the
risk of the disease or disorder).
[0323] Administration of the compositions of the present invention
to a subject to be treated can be carried out using known
procedures, at dosages and for periods of time effective to inhibit
amyloid deposition in the subject. An effective amount of the
therapeutic compound necessary to achieve a therapeutic effect may
vary according to factors such as the amount of amyloid already
deposited at the clinical site in the subject, the age, sex, and
weight of the subject, and the ability of the therapeutic compound
to inhibit amyloid deposition in the subject. Dosage regimens can
be adjusted to provide the optimum therapeutic response. For
example, several divided doses may be administered daily or the
dose may be proportionally reduced as indicated by the exigencies
of the therapeutic situation. A non-limiting example of an
effective dose range for a therapeutic compound of the invention
(e.g., 3-amino-1-propanesulfonic acid) is between 1 and 500 mg/kg
of body weight/per day. One of ordinary skill in the art would be
able to study the relevant factors and make the determination
regarding the effective amount of the therapeutic compound without
undue experimentation.
[0324] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0325] In particular, the selected dosage level will depend upon a
variety of factors including the activity of the particular
compound of the present invention employed, the time of
administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds or materials used in combination with the particular
compound employed, the age, sex, weight, condition, general health
and prior medical history of the patient being treated, and like
factors well known in the medical arts.
[0326] A medical doctor, e.g., physician or veterinarian, having
ordinary skill in the art can readily determine and prescribe the
effective amount of the pharmaceutical composition required. For
example, the physician or veterinarian could start doses of the
compounds of the invention employed in the pharmaceutical
composition at levels lower than that required in order to achieve
the desired therapeutic effect and gradually increase the dosage
until the desired effect is achieved.
[0327] The regimen of administration can affect what constitutes an
effective amount. The therapeutic formulations can be administered
to the subject either prior to or after the onset of amyloidosis.
Further, several divided dosages, as well as staggered dosages, can
be administered daily or sequentially, or the dose can be
continuously infused, or can be a bolus injection. Further, the
dosages of the therapeutic formulations can be proportionally
increased or decreased as indicated by the exigencies of the
therapeutic or prophylactic situation.
[0328] In particular embodiments, it is especially advantageous to
formulate compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subjects to be treated; each unit containing a
predetermined quantity of therapeutic compound calculated to
produce the desired therapeutic effect in association with the
required pharmaceutical vehicle. The specification for the dosage
unit forms of the invention are dictated by and directly dependent
on (a) the unique characteristics of the therapeutic compound and
the particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding/formulating such a
therapeutic compound for the treatment of amyloid deposition in
subjects.
[0329] A further aspect of the invention includes pharmaceutical
compositions for treating amyloidosis; inhibiting amyloid
deposition; or preventing or treating amyloid-related disease,
e.g., A.beta.-related disease, e.g., Alzheimer's disease, cerebral
amyloid angiopathy, inclusion body myositis, macular degeneration,
Down's syndrome, Mild Cognitive Impairment, and hereditary cerebral
hemorrhage. The therapeutic formulations described hereinbefore,
can be incorporated into a pharmaceutical composition containing a
pharmaceutically acceptable vehicle and an amount of a therapeutic
compound formulated to significantly reduce or prevent
gastrointestinal intolerance, in an amount sufficient to treat or
inhibit amyloidosis; inhibit amyloid deposition; or prevent or
treat amyloid-related disease. In one embodiment, the
pharmaceutical compositions of the invention include a therapeutic
compound having the formula 3-amino-1-propanesulfonate/X, where X
is an ester or a counter cation, wherein the ester or counter
cation includes alcohol radicals or positively charged atoms and
moieties, respectively, that do not significantly affect the
ability of the therapeutic formulation to reduce or prevent
gastrointestinal intolerance. In a preferred embodiment, the
cationic group is hydrogen, H.sup.+, and the compound is
3-amino-1-propanesulfonic acid.
[0330] In yet another embodiment, the invention is a method of
formulating a gastrointestinal intolerance enhanced pharmaceutical
composition comprising: combining a pre-selected therapeutic
compound with a pharmaceutically acceptable carrier, wherein the
therapeutic compound is pre-selected for its ability to
significantly reduce or prevent gastrointestinal intolerance,
forming a gastrointestinal intolerance enhanced pharmaceutical
composition.
[0331] The language "gastrointestinal intolerance enhanced
pharmaceutical composition" includes pharmaceutical compositions
containing therapeutic compounds of the invention that have been
chosen by pre-selecting the compound based on its ability to
significantly reduce or prevent gastrointestinal intolerance.
[0332] IV. Administration
[0333] Formulations of the present invention include those suitable
for oral administration. The formulations may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of active ingredient
which can be combined with a carrier material to produce a single
dosage form will generally be that amount of the compound which
produces a therapeutic effect. Generally, out of one hundred
percent, this amount will range from about 1 percent to about
ninety-nine percent of active ingredient, preferably from about 5
percent to about 70 percent, most preferably from about 10 percent
to about 30 percent.
[0334] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0335] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) or as mouth washes and the like,
each containing a predetermined amount of a compound of the present
invention as an active ingredient. A compound of the present
invention may also be administered as a bolus, electuary or
paste.
[0336] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate
or dicalcium phosphate, or any of the following: fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
or silicic acid; binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose or acacia; humectants, such as glycerol; disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate;
solution retarding agents, such as paraffin; absorption
accelerators, such as quaternary ammonium compounds; wetting
agents, such as, for example, cetyl alcohol and glycerol
monostearate; absorbents, such as kaolin and bentonite clay;
lubricants, such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and coloring agents. In the case of capsules, tablets and
pills, the pharmaceutical compositions may also comprise buffering
agents. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0337] The therapeutic compounds of the invention are effective
when administered orally. Accordingly, a preferred route of
administration is oral administration. The therapeutically active
compound may be coated in a material to protect the compound from
the action of acids and other natural conditions which may
inactivate the compound. The compounds of the invention can be
formulated to ensure proper distribution in vivo. For example, the
blood-brain barrier (BBB) excludes many highly hydrophilic
compounds; and to ensure that the therapeutic compounds of the
invention cross the BBB, they can be formulated, for example, in
liposomes. For methods of manufacturing liposomes, see, e.g., U.S.
Pat. Nos. 4,522,811; 5,374,548; and 5,399,331. The liposomes may
comprise one or more moieties which are selectively transported
into specific cells or organs ("targeting moieties"), thus
providing targeted drug delivery (see, e.g., V. V. Ranade (1989) J.
Clin. Pharmacol. 29: 685). Exemplary targeting moieties include
folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et
al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res.
Commun. 153: 1038); antibodies (P. G. Bloeman et al. (1995) FEBS
Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents
Chemother. 39: 180); surfactant protein A receptor (Briscoe et al.
(1995) Am. J. Physiol. 1233: 134); gp120 (Schreier et al. (1994) J.
Biol. Chem. 269: 9090); see also K. Keinanen; M. L. Laukkanen
(1994) FEBS Lett. 346: 123; J. J. Killion; I. J. Fidler (1994)
Immunomethods 4: 273.
[0338] To administer the therapeutic compound it may be necessary
to coat the compound with, or co-administer the compound with, a
material to prevent its inactivation. For example, the therapeutic
compound may be administered to a subject in an appropriate
carrier, for example, liposomes, or a diluent. Liposomes include
water-in-oil-in-water CGF emulsions as well as conventional
liposomes (Strejan, et al., J Neuroimmunol. 7, 27 (1984)).
[0339] The therapeutic compound can be orally administered, for
example, with an inert diluent or an assimilable edible carrier.
The therapeutic compound and other ingredients may also be enclosed
in a hard or soft shell gelatin capsule, compressed into tablets,
or incorporated directly into the subject's diet. For oral
therapeutic administration, the therapeutic compound may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. The percentage of the therapeutic
compound in the compositions and preparations may, of course, be
varied. The amount of the therapeutic compound in such
therapeutically useful compositions is such that a suitable dosage
will be obtained.
[0340] The term "pharmaceutically acceptable carrier" includes a
pharmaceutically acceptable material, composition or vehicle, such
as a liquid or solid filler, diluent, excipient, solvent or
encapsulating material, involved in carrying or transporting a
compound(s) of the present invention within or to the subject such
that it can perform its intended function. Typically, such
compounds are carried or transported from one organ, or portion of
the body, to another organ, or portion of the body. Each carrier
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation, not injurious to the patient,
and in the sense that it does not affect the ability of the
therapeutic formulation to reduce or prevent gastrointestinal
intolerance. Some examples of materials which can serve as
pharmaceutically acceptable carriers include: sugars, such as
lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer
solutions; and other non-toxic compatible substances employed in
pharmaceutical formulations known in the art.
[0341] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0342] Examples of pharmaceutically acceptable antioxidants
include: water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0343] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0344] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents, and/or may contain agents
that release the active ingredient(s) only, or preferentially, in a
certain portion of the gastrointestinal tract, optionally, in a
delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0345] Powders can contain, in addition to a compound of this
invention, excipients such as lactose, talc, silicic acid, aluminum
hydroxide, calcium silicates and polyamide powder, or mixtures of
these substances.
[0346] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof. Besides inert
diluents, the oral compositions can also include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening,
flavoring, coloring, perfuming and preservative agents.
[0347] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0348] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents that delay
absorption such as aluminum monostearate and gelatin.
[0349] The compositions of this invention can also be administered
topically to a subject, e.g., by the direct laying on or spreading
of the composition on the epidermal or epithelial tissue of the
subject, or transdermally via a "patch". Such compositions include,
for example, lotions, creams, solutions, gels and solids. These
topical compositions preferably comprise an effective amount,
usually at least about 0.1%, and preferably from about 1% to about
5%, of a compound of the invention. Suitable carriers for topical
administration preferably remain in place on the skin as a
continuous film, and resist being removed by perspiration or
immersion in water. Generally, the carrier is organic in nature and
capable of having the therapeutic compound dispersed or dissolved
therein. The carrier may include pharmaceutically acceptable
emolients, emulsifiers, thickening agents, solvents and the
like.
[0350] In one embodiment, the pharmaceutical formulation comprises
greater than about 0.1%, e.g., greater than about 1%, e.g., greater
than about 2%, e.g., greater than about 3%, e.g., greater than
about 4%, e.g., greater than about 5%, e.g., greater than about
10%, e.g., greater than about 20%, e.g., greater than about 30%,
e.g., greater than about 40%, e.g., greater than about 50%, e.g.,
greater than about 60%, e.g., greater than about 70%, e.g., greater
than about 80%, e.g., greater than about 90%, e.g., greater than
about 95%, e.g., greater than about 99%, of a therapeutic compound,
e.g., an alkylsulfonic acid, e.g., a 3-amino-1-propanesulfonic acid
compound, by weight of the formulation. In a specific embodiment,
the pharmaceutical formulation comprises about 12.6%+0.5% of the
therapeutic compound by weight of the formulation. In another
specific embodiment, the pharmaceutical formulation comprises about
95.2%+0.5% of the therapeutic compound by weight of the
formulation. The remainder of the pharmaceutical formulation may be
comprised of additional agents as described herein.
[0351] In another embodiment, the pharmaceutical formulation
comprises greater than about 1%, e.g., greater than about 2%, e.g.,
greater than about 3%, e.g., greater than about 4%, e.g., greater
than about 5%, e.g., greater than about 6%, e.g., greater than
about 7%, e.g., greater than about 8%, e.g., greater than about 9%,
e.g., greater than about 10%, e.g., greater than about 20%, e.g.,
greater than about 30%, e.g., greater than about 40%, e.g., greater
than about 50%, e.g., greater than about 60%, e.g., greater than
about 70%, e.g., greater than about 80%, e.g., greater than about
90%, e.g., greater than about 95%, e.g., greater than about 99%, of
an additional agent, e.g., an agent that modifies the release of
the therapeutic compound or an enteric coating, by weight of the
formulation. It should be understood that these percentages are
ranges that apply to the one or more additional agents of the
formulation, independently or in combination. In certain
embodiments the additional agent may be used in the therapeutic
formulation to impart favorable properties, e.g., to reduce or
prevent gastrointestinal intolerance independently or in
conjunction with other methods of reducing or preventing
intolerance. Exemplary additional agents are described herein. For
example, to protect against any possible gastrointestinal
intolerance that could result from the therapeutic formulation, the
tablets may be enteric-coated or a modified-release agent may be
added to control any rapid release of the therapeutic compound in
the stomach or intestine. In a specific embodiment, the
pharmaceutical formulation comprises about 9.3%.+-.0.5% of the
additional agent by weight of the formulation. In another specific
embodiment, the pharmaceutical formulation comprises about
8.8%.+-.0.5% of the additional agent by weight of the formulation.
In another specific embodiment, the pharmaceutical formulation
comprises about 5.6%.+-.0.5% of the additional agent by weight of
the formulation.
[0352] In specific embodiments of the invention, the therapeutic
compound is administered with an agent selected from the group
consisting of an agent that modifies the release of the therapeutic
compound, e.g., hydroxypropylmethylcellulose (HPMC), a
glidant/diluent, e.g., silicated mycrocrystalline, a filler, e.g.,
dibasic calcium phosphate, a binder/desintegrant, e.g., Starch.RTM.
1500, a lubricant, e.g., stearic acid powder or magnesium stearate,
a subcoat, e.g., Opadry.RTM. II White, a topcoat, e.g., Opadry.RTM.
H White or Opadry.RTM. Clear, an enteric coat, e.g., Acryleze.RTM.,
and any combination thereof. The following materials are available
from Colorcon (West Point, Pa.): Starch.RTM. 1500, Opadry.RTM. II
White, Opadry.RTM. Clear, Acryleze.RTM.. Several embodiments of the
invention are discussed below in the Exemplification.
[0353] Equivalents
[0354] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation and the
content of the instant specification, numerous equivalents to the
specific procedures, embodiments, claims, and examples described
herein. Such equivalents are considered to be within the scope of
this invention and covered by the claims appended hereto.
[0355] It is to be understood that wherever values and ranges are
provided herein, e.g., in ages of subject populations, dosages, and
blood levels, all values and ranges encompassed by these values and
ranges, are meant to be encompassed within the scope of the present
invention. Moreover, all values that fall within these ranges, as
well as the upper or lower limits of a range of values are also
contemplated by the present application.
[0356] Incorporation by Reference
[0357] The contents of all references, issued patents, and
published patent applications cited throughout this application are
hereby incorporated by reference. It should be understood that the
use of any of the compounds described herein or in the applications
identified in "The Related Applications" Section are within the
scope of the present invention and are intended to be encompassed
by the present invention and are expressly incorporated herein at
least for these purposes, and are furthermore expressly
incorporated for all other purposes.
EXAMPLES
[0358] The invention is further illustrated by the following
examples which should not be construed as further limiting the
subject invention.
Example 1
Gelatin Capsules for Oral Administration
[0359] The unit formula of 100 and 400 mg white gelatin capsules is
presented in Table 2.
2TABLE 2 Unit Formula for 100 and 400 mg Gelatin Capsules Capsules
(mg/capsule) Ingredient Grade Function 100 mg 400 mg
3-amino-1-propanesulfonic MS* Active 100 mg 400 mg acid, sodium
salt Ingredient Calcium carbonate NF Filler 4.45 17.8 Magnesium
stearate NF Lubricant 0.55 2.2 *MS: Manufacturer's Standard, NF:
National Formulary; USP: United States Pharmacopoeia.
[0360] Results from certain studies have shown that the
administration of 3-amino-1-propanesulfonic acid sodium salt in
solid dosage form (capsules) was associated with gastrointestinal
symptoms (i.e. nausea and vomiting). Further investigations
revealed that the gastrointestinal symptoms were produced, at least
in part, by a local irritation due to the high pH generated during
the dissolution of amino-1-propanesulfonic acid sodium salt into
the stomach. Additional experiments in dogs (in solid dosage form)
have shown that the free acid was better tolerated than the sodium
salt form. Furthermore, the non-hygroscopic nature of the acid form
makes it desirable as active pharmaceutical ingredient. To further
protect against any possible gastrointestinal intolerance that
could result from the acid form, the tablets were enteric-coated
and a modified-release agent was added to control any rapid release
of the drug in the stomach and the intestine, respectively.
Example 2
Enteric-Coated Tablets
[0361] The 100 and 400 mg white enteric-coated tablets were
prepared according to a formulation in which the drug substance
produced by a process utilizing ion-exchange to remove sodium was
densified by granulation with water because of its low density and
fluffiness. The unit formula of the 100 and 400 mg Enteric-Coated
tablets is presented in Table 3.
3TABLE 3 Unit Formula of 100 and 400 Enteric-Coated Tablets
Enteric-Coated Tablet (mg/tablet) Ingredient Grade Function 100 mg
400 mg Core: 3-amino-1-propanesulfonic acid MS* Active Ingredient
100.00 400.00 Silicated mycrocrystalline cellulose NF
Glidant/Diluent 350.00 70.00 Dibasic calcium phosphate USP Filler
158.40 112.00 Hydroxypropylmethylcellulose (HPMC) USP Drug Release
Modifier 70.00 70.00 Starch .RTM. 1500 NF Binder/Desintegrant 11.10
37.50 Stearic acid powder NF Lubricant 7.00 7.00 Magnesium stearate
NF Lubricant 1.80 0.018 Coating: Opadry .RTM. II White MS* Subcoat
14.00 14.00 Acryleze .RTM. MS* Enteric Coat 42.00 42.00 Total
Weight: 756.00 756.00 *MS: Manufacturer's Standard, NF: National
Formulary; USP: United States Pharmacopoeia.
[0362] In vitro (dissolution rate) and PK data from 100 mg
enteric-coated tablets used in initial Phase I studies indicated
that these tablets would result in acceptable PK and good
tolerability.
Example 3
Modified-Release Coated Tablets
[0363] Clinical studies indicated that the role of the
enteric-coating and drug release modifier would be significant in
the pharmacokinetic (PK) profile of the drug product as well as its
tolerability. Accordingly, in order to give particular
pharmaceutical performance in terms of PK, tolerability and product
stability, drug release modifier was formulated into the
tablet.
[0364] To improve physical stability of the product in terms of
film coating acceptability and moisture protection capability,
under accelerated conditions, the enteric-coating system was
modified by the increase in the amount of enteric-coating and the
addition of a topcoat.
[0365] A 50 mg strength modified-release coated tablet consisting
of bulk substance (3-amino-1-propanesulfonic acid) and inactive
ingredients (silicated mycrocrystalline cellulose, dibasic calcium
phosphate, hydroxypropylmethylcellulose, starch, stearic acid,
magnesium stearate, as well as Opadry.RTM. II white (subcoat and
topcoat) and Acryleze.RTM.) was prepared. The unit formula of the
50 mg modified-release coated tablet is provided in Table 4.
4TABLE 4 Unit Formula of 50 mg Modified-Release Coated Tablets
Quantity per Quantity per tablet batch Ingredient Grade Function
(mg) (kg) Core: 3-amino-1-propanesulfonic acid MS* Active
Ingredient 50.00 0.500 Silicated mycrocrystalline cellulose NF
Glidant/Diluent 174.73 1.746 Dibasic calcium phosphate USP Filler
79.42 0.794 Hydroxypropylmethylcellulose USP Drug Release 35.00
0.350 (HPMC) Modifier Starch .RTM. 1500 NF Binder/Desintegrant 5.55
0.056 Stearic acid powder NF Lubricant 3.50 0.036 Magnesium
stearate NF Lubricant 1.80 0.018 Weight: 350.00 3.500 Coating: --
Opadry .RTM. II White MS* Subcoat 7.00 0.072 Acryleze .RTM. MS*
Enteric Coat 35.00 0.360 Opadry .RTM. Clear MS* Topcoat 3.50 0.036
Total Weight: 395.50 3.974 *MS: Manufacturer's Standard, NF:
National Formulary; USP: United States Pharmacopoeia.
Example 4
Modified-Release Coated Tablets
[0366] A slight modification to the coating in the formulation of
Example 3 was made: the Opadry.RTM. Clear used as the topcoat in
Example 3 was replaced by Opadry.RTM. II White, which is also used
for the subcoat. Like Opadry.RTM. Clear, Opadry.RTM. II White is an
HPMC-based preparation which functions in a sealing capacity and
therefore equally functions to enhance the moisture protection
capability of the enteric coat (Acryleze.RTM.). The coating system
change of the topcoat was a process change that may be convenient
for the scale-up of the product formulation size, i.e., to
facilitate the transition from applying one coat to the other
during the coating process by preventing clogging of spray guns
during the transition from the enteric coating step to the topcoat
application step during the coating process.
[0367] The unit formula for the 50 mg modified-release coated
tablets are represented in Table 5.
5TABLE 5 Unit Formula of 50 mg Modified-Release Coated Tablets
Quantity Quantity per tablet per batch Ingredient Grade Function
(mg) (kg) Core: 3-amino-1-propanesulfonic acid MS* Active
ingredient 50.00 0.500 Silicated mycrocrystalline cellulose NF
Glidant/Diluent 174.73 1.746 Dibasic calcium phosphate USP Filler
79.42 0.794 Hydroxypropylmethylcellulose USP Drug Release 35.00
0.350 (HPMC) Modifier Starch .RTM. 1500 NF Binder/Desintegrant 5.55
0.056 Stearic acid powder NF Lubricant 3.50 0.036 Magnesium
stearate NF Lubricant 1.80 0.018 Weight: 350.00 3.500 Coating: --
Opadry .RTM. II White MS* Subcoat 7.00 0.072 Acryleze .RTM. MS*
Enteric Coat 35.00 0.360 Opadry .RTM. II White MS* Topcoat 3.50
0.036 Total Weight: 395.50 3.974 *MS: Manufacturer's Standard, NF:
National Formulary; USP: United States Pharmacopoeia.
[0368] The dissolution profile, carried out according to the USP
method (USP 25, Method B, p. 2017), indicates that the dissolution
rate for both of the 50 mg modified release coated tablets
(Examples 3 and 4) is comparable.
[0369] In addition, in order to improve the stability of appearance
i.e., whiteness, the following modified release coated tablet
formulation was prepared, i.e., with increased Opadry.RTM. II
White:
6TABLE 6 Unit Formula of 50 mg Modified-Release Coated Tablets
Quantity Quantity per tablet per batch Ingredient Grade Function
(mg) (kg) Core: 3-amino-1-propanesulfonic acid MS* Active
ingredient 50.00 0.500 Silicated mycrocrystalline cellulose NF
Glidant/Diluent 174.73 1.746 Dibasic calcium phosphate USP Filler
79.42 0.794 Hydroxypropylmethylcellulose USP Drug Release 35.00
0.350 (HPMC) Modifier Starch .RTM. 1500 NF Binder/Desintegrant 5.55
0.056 Stearic acid powder NF Lubricant 3.50 0.036 Magnesium
stearate NF Lubricant 1.80 0.018 Weight: 350.00 3.500 Coating: --
Opadry .RTM. II White MS* Subcoat 7.00 0.072 Acryleze .RTM. MS*
Enteric Coat 35.00 0.360 Opadry .RTM. II White MS* Topcoat 7.00
0.072 Total Weight: 399.00 4.004 *MS: Manufacturer's Standard, NF:
National Formulary; USP: United States Pharmacopoeia.
Example 5
Mass Spectroscopy Assay
[0370] The binding of a compound to amyloid fibrils may be measured
using a mass spectroscopy ("MS") assay as described herein
below.
[0371] Samples are prepared as aqueous solutions containing 20%
ethanol, 200 .mu.M of a test compound and 20 .mu.M of solubilized
A.beta.40. The pH value of each sample is adjusted to 7.4 (.+-.0.2)
by addition of 0.1% aqueous sodium hydroxide. The solutions are
then analyzed by electrospray ionization mass spectroscopy using a
Waters ZQ 4000 mass spectrometer. Samples are introduced by direct
infusion at a flow-rate of 25 .mu.L/min within 2 hr. after sample
preparation. The source temperature is kept at 70.degree. C. and
the cone voltage is 20 V for all the analysis. Data is processed
using Masslynx 3.5 software. The resulting MS assay data provides
insight into the ability of compounds to bind to A.beta..
* * * * *