U.S. patent application number 17/805280 was filed with the patent office on 2022-09-22 for treatment of focal segmental glomerulosclerosis with ccr2 antagonists.
The applicant listed for this patent is CHEMOCENTRYX, INC.. Invention is credited to Zhenhua MIAO, Thomas J. Schall, Rajinder Singh.
Application Number | 20220296601 17/805280 |
Document ID | / |
Family ID | 1000006380990 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220296601 |
Kind Code |
A1 |
MIAO; Zhenhua ; et
al. |
September 22, 2022 |
TREATMENT OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS WITH CCR2
ANTAGONISTS
Abstract
Provided herein are methods of treating focal segmental
glomerulosclerosis, said methods include administering to a subject
in need thereof a therapeutically effective amount of a CCR2
antagonist. In some embodiments, the CCR2 antagonist is used in
monotherapy. In some embodiments, the CCR2 antagonist is used in
combination therapy. In some embodiments, the additional
therapeutic agent is a RAAS blocker and/or an endothelin receptor
inhibitor.
Inventors: |
MIAO; Zhenhua; (San Carlos,
CA) ; Schall; Thomas J.; (San Carlos, CA) ;
Singh; Rajinder; (Belmont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHEMOCENTRYX, INC. |
San Carlos |
CA |
US |
|
|
Family ID: |
1000006380990 |
Appl. No.: |
17/805280 |
Filed: |
June 3, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16990100 |
Aug 11, 2020 |
11382915 |
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17805280 |
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16156608 |
Oct 10, 2018 |
10758540 |
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16990100 |
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62570778 |
Oct 11, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/41 20130101;
A61K 31/437 20130101; A61P 13/12 20180101; A61K 31/519 20130101;
A61K 31/422 20130101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/41 20060101 A61K031/41; A61P 13/12 20060101
A61P013/12; A61K 31/437 20060101 A61K031/437; A61K 31/422 20060101
A61K031/422 |
Claims
1. A method of reducing urinary albumin excretion rate (UAER), the
method comprising administering to a subject in need thereof a
therapeutically effective amount of a CCR2 antagonist, wherein the
CCR2 antagonist is a compound of Formula II ##STR00007## or a
pharmaceutically acceptable form thereof, wherein R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-8 alkyl, CN, or C.sub.1-8 haloalkyl,
provided that at least one of R.sup.1 or R.sup.2 is other than
hydrogen; R.sup.5 is halogen or C.sub.1-8 alkyl; X.sup.2 is
CR.sup.7, N, or NO; R.sup.7 is independently selected from the
group consisting of hydrogen, halogen, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, --CN, --NO.sub.2, --OR.sup.8,
--OC(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)R.sup.8,
--C(O)NR.sup.9R.sup.8, --OC(O)NR.sup.9R.sup.8,
--NR.sup.10C(O)R.sup.8, --NR.sup.10C(O)NR.sup.9R.sup.8,
--NR.sup.9R.sup.8, --NR.sup.10CO.sub.2R.sup.8, --SR.sup.8,
--S(O)R.sup.8, --S(O).sub.2R.sup.8, --S(O).sub.2NR.sup.9R.sup.8,
--NR.sup.10S(O).sub.2R.sup.8, C.sub.6-10 aryl, 5- to 10-membered
heteroaryl and 3- to 10-membered heterocyclyl; each R.sup.8,
R.sup.9 and R.sup.10 is independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, aryl, or heteroaryl; or R.sup.9 and R.sup.8 or
R.sup.10 and R.sup.8, together with the atom(s) to which they are
attached, form a 5-, 6-, or 7-membered ring; and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10 aryl, 5- to
10-membered heteroaryl and 3- to 10-membered heterocycle, wherein
the CCR2 antagonist is administered in combination with one or more
additional therapeutic agents, the one or more additional
therapeutic agents being a Renin-angiotensin-aldosterone (RAAS)
blocker or an endothelin receptor antagonist.
2. The method of claim 1, wherein R.sup.1 and R.sup.2 are each
independently selected from the group consisting of halogen,
C.sub.1-8 alkyl, or C.sub.1-8 haloalkyl, provided that at least one
of R.sup.1 or R.sup.2 is other than hydrogen; R.sup.5 is halogen or
C.sub.1-8 alkyl; X.sup.2 is CR.sup.7 or N; R.sup.7 is independently
selected from the group consisting of hydrogen, halogen, C.sub.1-8
alkyl, --CN, --NO.sub.2, --OR.sup.8, and --NR.sup.9R.sup.8;
R.sup.11 is hydrogen or C.sub.1-8 alkyl.
3. The method of claim 1, wherein R.sup.1 is halogen
R.sup.2C.sub.1-8 haloalkyl; R.sup.5 is C.sub.1-8 alkyl; X.sup.2 is
CR.sup.7 or N; R.sup.7 is independently selected from the group
consisting of hydrogen, halogen, C.sub.1-8 alkyl; R.sup.11 is
hydrogen or C.sub.1-8 alkyl.
4. The method of claim 1, wherein R.sup.1 is chloro R.sup.2
trifluoromethyl; R.sup.5 is methyl; X.sup.2 is CR.sup.7 or N;
R.sup.7 is independently selected from the group consisting of
hydrogen, halogen, C.sub.1-8 alkyl; R.sup.11 is hydrogen or
C.sub.1-8 alkyl.
5. The method of claim 1, wherein the compound of Formula II has
the structure of Compound 1 ##STR00008## or a pharmaceutically
acceptable form thereof.
6. The method of claim 1, wherein the compound of Formula II has
the structure of Compound 2 ##STR00009## or a pharmaceutically
acceptable form thereof.
7. The method of claim 1, wherein the CCR2 antagonist is
administered daily.
8. The method of claim 1, wherein the effective amount of the
compound of Formula II is 5 mg administered twice daily.
9. The method of claim 1, wherein the effective amount of the
compound of Formula II is 10 mg administered twice daily.
10. The method of claim 1, wherein the additional therapeutic agent
is a Renin-angiotensin-aldosterone (RAAS) blocker.
11. The method of claim 10, wherein the RAAS blocker is a renin
inhibitor.
12. The method of claim 11, wherein the renin inhibitor is selected
from the group consisting of aliskiren, remikiren, H-142, SPP635,
SPP1148, SPP676, and SPP1234.
13. The method of claim 10, wherein the RAAS blocker is an ACE
inhibitor.
14. The method of claim 13, wherein the ACE inhibitor is enazepril,
captopril, enalapril, fosinopril, lisinopril, perindopril,
quinapril, rampipril, and trandolapril.
15. The method of claim 10, wherein the RAAS blocker an angiotensin
receptor blocker (ARB).
16. The method of claim 15, wherein the ARB is selected from the
group consisting of sparsentan, eprosartan, candesartan,
irbesartan, losartan, olmesartan, telmisartan, valsartan,
CGP-42112A, DuP753, saralasin, and sarthran.
17. The method of claim 15, wherein the ARB is selected from the
group consisting of eprosartan, candesartan, irbesartan, losartan,
olmesartan, telmisartan, valsartan, CGP-42112A, DuP753, saralasin,
and sarthran.
18. The method of claim 1, wherein the additional therapeutic agent
is an endothelin receptor antagonist, wherein the endothelin
receptor antagonist is selected from the group consisting of
sparsentan, bosentan, macitentan, ambrisentan, sitazentan,
aprocitentan, and artasentan.
19. The method of claim 1, wherein the subject is being treated for
diabetic nephropathy.
20. A method of reducing urine-to-creatinine ratio in a subject,
the method comprising administering to the subject in need thereof
a therapeutically effective amount of a CCR2 antagonist, wherein
the CCR2 antagonist is a compound of Formula II ##STR00010## or a
pharmaceutically acceptable form thereof, wherein R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-8 alkyl, CN, or C.sub.1-8 haloalkyl,
provided that at least one of R.sup.1 or R.sup.2 is other than
hydrogen; R.sup.5 is halogen or C.sub.1-8 alkyl; X.sup.2 is
CR.sup.7, N, or NO; R.sup.7 is independently selected from the
group consisting of hydrogen, halogen, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, --CN, --NO.sub.2, --OR.sup.8,
--OC(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)R.sup.8,
--C(O)NR.sup.9R.sup.8, --OC(O)NR.sup.9R.sup.8,
--NR.sup.10C(O)R.sup.8, --NR.sup.10C(O)NR.sup.9R.sup.8,
--NR.sup.9R.sup.8, --NR.sup.10CO.sub.2R.sup.8, --SR.sup.8,
--S(O)R.sup.8, --S(O).sub.2R.sup.8, --S(O).sub.2NR.sup.9R.sup.8,
--NR.sup.10S(O).sub.2R.sup.8, C.sub.6-10 aryl, 5- to 10-membered
heteroaryl and 3- to 10-membered heterocyclyl; each R.sup.8,
R.sup.9 and R.sup.10 is independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, aryl, or heteroaryl; or R.sup.9 and R.sup.8 or
R.sup.10 and R.sup.8, together with the atom(s) to which they are
attached, form a 5-, 6-, or 7-membered ring; and R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10 aryl, 5- to
10-membered heteroaryl and 3- to 10-membered heterocycle, wherein
the CCR2 antagonist is administered in combination with one or more
additional therapeutic agents, the one or more additional
therapeutic agents being a Renin-angiotensin-aldosterone (RAAS)
blocker or an endothelin receptor antagonist.
21. The method of claim 20, wherein the compound of Formula II is
selected from the group consisting of: ##STR00011## and a
pharmaceutically acceptable form thereof.
22. The method of claim 20, wherein the subject is being treated
for diabetic nephropathy.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 16/990,100, filed Aug. 11, 2020, which
is a continuation application of U.S. patent application Ser. No.
16/156,608, filed Oct. 10, 2018, which claims benefit under 35
U.S.C. .sctn. 119(e) of U.S. Provisional Application No. 62/570,778
filed Oct. 11, 2017, both of which are incorporated herein by
reference in their entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] Not Applicable
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] Focal segmental glomerulosclerosis (FSGS) comprises a group
of uncommon disorders that present with marked proteinuria,
nephrotic syndrome, progressive renal failure and characteristic
glomerular lesions on histopathology. The current standard of care
for patients with FSGS include immunosuppressive drugs such as
glucocorticoids followed by calcineurin inhibitors, if needed, for
intolerance or inadequate response to glucocorticoids.
Renin-angiotensin-aldosterone (RAAS) blockers are also used to
control proteinuria, an important signature of FSGS. Existing
treatments, however, achieved only limited success. Despite best
care, treatment failure is common and FSGS is causal in a
significant proportion of end stage renal disease. Thus, an unmet
need exists for novel disease modifying treatments for FSGS.
BRIEF SUMMARY OF THE INVENTION
[0005] Provided herein are methods of treating focal segmental
glomerulosclerosis, said methods comprising administering to a
subject in need thereof a therapeutically effective amount of a
CCR2 antagonist.
[0006] In some embodiments, the CCR2 antagonist is a compound of
Formula I
##STR00001##
or a pharmaceutically acceptable form thereof, wherein [0007]
R.sup.1 and R.sup.2 are each independently selected from the group
consisting of hydrogen, halogen, C.sub.1-8 alkyl, CN, or C.sub.1-8
haloalkyl, provided that at least one of R.sup.1 or R.sup.2 is
other than hydrogen; [0008] R.sup.5 is halogen or C.sub.1-8 alkyl;
[0009] R.sup.6 is hydrogen or C.sub.1-8 alkyl; [0010] X.sup.1 and
X.sup.2 are each independently is CR.sup.7, N, or NO; [0011]
X.sup.4 is N or NO; [0012] X.sup.3 is CR.sup.7; [0013] X.sup.6 and
X.sup.7 are each independently selected from CR.sup.7, N, and NO;
[0014] R.sup.7 is independently selected from the group consisting
of hydrogen, halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, --CN, --NO.sub.2, --OR.sup.8, --OC(O)R.sup.8,
--CO.sub.2R.sup.8, --C(O)R.sup.8, --C(O)NR.sup.9R.sup.8,
--OC(O)NR.sup.9R.sup.8, --NR.sup.10C(O)R.sup.8,
--NR.sup.10C(O)NR.sup.9R.sup.8, --NR.sup.9R.sup.8,
--NR.sup.10CO.sub.2R.sup.8, --SR.sup.8, --S(O)R.sup.8,
--S(O).sub.2R.sup.8, --S(O).sub.2NR.sup.9R.sup.8,
--NR.sup.10S(O).sub.2R.sup.8, C.sub.6-10 aryl, 5- to 10-membered
heteroaryl and 3- to 10-membered heterocyclyl; [0015] each R.sup.8,
R.sup.9 and R.sup.10 is independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, aryl, or heteroaryl; or R.sup.9 and R.sup.8 or
R.sup.10 and R.sup.8, together with the atom(s) to which they are
attached, form a 5-, 6-, or 7-membered ring; R.sup.11 is selected
from the group consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, C.sub.6-10 aryl, 5- to 10-membered
heteroaryl and 3- to 10-membered heterocycle.
[0016] In some embodiments, the CCR2 antagonist is a compound of
Formula II
##STR00002##
[0017] In some embodiments, the CCR2 antagonists are administered
in combination with an additional therapeutic agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 illustrates the titration of Compound 1 and the
inhibition of radio-labeled mJE binding to WEHI cells. Compound 1
was added at the indicated concentrations and competed with the
binding of murine CCL2 (JE) to the cells, as described in Methods.
The IC.sub.50 was determined to be 270 nM.
[0019] FIG. 2 illustrates the pharmacokinetic profile of Compound 1
in mice. Compound 1 was administered by s.c. injection and the
concentration in the blood was determined. Measured levels for 30
mg/kg (black circles) and 90 mg/kg (black squares) are shown.
[0020] FIGS. 3A-3D Compound 1 improves renal function in adriamycin
challenged mice. Mice were challenged with Adriamycin as described
in Methods. Test compound treatment was begun one hour prior to the
Adriamycin challenge. Urine was collected for measurement of
albumin and creatinine at the indicated time points (3A, week 1;
3B, week 2), as described in Methods. Serum creatinine (3C) and BUN
(3D) were measured at time of the terminal bleed after two weeks of
treatment. Error bars represent standard error of the mean.
N=10/group at week 1, and N=8 at week 2.
[0021] FIGS. 4A and 4B Compound 1 improves renal function in
partially nephrectomized mice. Mice underwent a 5/6 nephrectomy as
described in Methods. Three weeks post-surgery the mice were
randomized to the groups indicated above for the study period of 4
weeks. Urine was collected for measurement of albumin and
creatinine at week 1 (4A) and week 3 (4B), as described in Methods.
Error bars represent standard error of the mean. P<0.05: *;
P<0.01: **; P<0.001: ***; P value compared to vehicle;
P<0.01: ##P value compared to RAASb
[0022] FIGS. 5A and 5B Compound 1 attenuates the rise in serum
creatinine (5A) and BUN (5B) in partially nephrectomized mice.
Measurements were made at the 4-week time point. Error bars
represent standard error of the mean. P<0.05: *; P<0.01: **;
P value compared to vehicle.
[0023] FIGS. 6A-6D Histological analysis of kidneys from the 5/6
nephrectomy model. The kidneys (8 animals/treated groups) were
harvested 5 weeks after initiation of treatment, and fixed and
stained as described in Methods. The kidneys were harvested 5 weeks
after treatment began, and fixed and stained as described in
Methods. Vehicle treatment is shown FIG. 6A; Compound 1 treatment
is shown in FIG. 6B; RAAS blocker is shown in FIG. 6C; and
combination of Compound 1 & RAAS blocker are shown in FIG. 6D.
The magnification is 100.times.. The black cycle indicate areas of
hyaline deposition, black arrows denote tubular collapse, and black
arrowhead denotes tubular dilation.
[0024] FIGS. 7A-7D Histological analysis of kidneys from the 5/6
nephrectomy model. The kidneys (8 animals/treated groups) were
harvested 5 weeks after initiation of treatment, and fixed and
stained as described in Methods. Vehicle treatment is shown in FIG.
7A; Compound 1 treatment is shown FIG. 7B; RAAS blocker is shown in
FIG. 7C; and combination of Compound 1 & RAAS blocker are shown
FIG. 7D. The magnification is 400.times.. The black cycle indicate
areas of hyaline deposition, black arrows denote glomerular
sclerosis, and black arrowhead denotes mesangial expansion.
[0025] FIGS. 8A and 8B Relative efficacy of CCR2, RAAS, and
Endothelin Receptor Blockade in the 5/6 Nephrectomy Model. Mice
underwent a 5/6 nephrectomy as described in Methods. Three weeks
post-surgery the mice were randomized to the indicated groups for
the study period of 4 weeks. Urine was collected for measurement of
albumin and creatinine at week 1 (8A) and week 4 (8B), as described
in Methods. Error bars represent standard error of the mean.
N=10/group.
DETAILED DESCRIPTION OF THE INVENTION
I. General
[0026] Provided herein are methods of treating focal segmental
glomerulosclerosis using a CCR2 antagonist. CCR2 antagonists may be
administered as a monotherapy or in combination. In some
embodiments, CCR2 antagonists are administered as a monotherapy. In
some embodiments, CCR2 antagonists are administered in combination
with a Renin-angiotensin-aldosterone (RAAS) blocker. In some
embodiments, CCR2 antagonists are administered in combination with
an endothelin receptor antagonist. In some embodiments, CCR2
antagonists are administered in combination with a
Renin-angiotensin-aldosterone (RAAS) blocker and an endothelin
receptor antagonist.
II. Definitions
[0027] As used herein the term "alkyl", by itself or as part of
another substituent, means, unless otherwise stated, a straight or
branched chain hydrocarbon radical, having the number of carbon
atoms designated (i.e. C.sub.1-8 means one to eight carbons).
Examples of alkyl groups include methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,
n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers
to an unsaturated alkyl group having one or more double bonds.
Similarly, the term "alkynyl" refers to an unsaturated alkyl group
having one or more triple bonds. Examples of such unsaturated alkyl
groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The
term "cycloalkyl" refers to hydrocarbon rings having the indicated
number of ring atoms (e.g., C.sub.3-6cycloalkyl) and being fully
saturated or having no more than one double bond between ring
vertices. "Cycloalkyl" is also meant to refer to bicyclic and
polycyclic hydrocarbon rings such as, for example,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term
"heterocycloalkane", "heterocycloalkyl", or "heterocyclyl" refers
to a cycloalkyl group that contain from one to five heteroatoms
selected from N, O, and S, wherein the nitrogen and sulfur atoms
are optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. The heterocycloalkane may be a monocyclic, a bicyclic
or a polycylic ring system. Non limiting examples of
heterocycloalkane groups include pyrrolidine, imidazolidine,
pyrazolidine, butyrolactam, valerolactam, imidazolidinone,
hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine-S-oxide,
thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline,
thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene,
quinuclidine, and the like. A heterocycloalkane group can be
attached to the remainder of the molecule through a ring carbon or
a heteroatom.
[0028] As used herein, the term "alkylene" by itself or as part of
another substituent means a divalent radical derived from an
alkane, as exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--.
Typically, an alkyl (or alkylene) group will have from 1 to 24
carbon atoms, with those groups having 10 or fewer carbon atoms
being preferred in the present disclosure. A "lower alkyl" or
"lower alkylene" is a shorter chain alkyl or alkylene group,
generally having four or fewer carbon atoms. Similarly,
"alkenylene" and "alkynylene" refer to the unsaturated forms of
"alkylene" having double or triple bonds, respectively. The term
"heteroalkylene" refers to an alkylene group in which one or two
carbon atoms are replaced by N, O, or S.
[0029] As used herein, a wavy line, "", that intersects a single,
double or triple bond in any chemical structure depicted herein,
represent the point attachment of the single, double, or triple
bond to the remainder of the molecule.
[0030] As used herein, the terms "halo" or "halogen," by themselves
or as part of another substituent, mean, unless otherwise stated, a
fluorine, chlorine, bromine, or iodine atom. Additionally, terms
such as "haloalkyl" and "haloalkoxy," are meant to include
monohalo- and polyhalo-versions of alkyl and alkoxy, respectively.
For example, the term "C.sub.1-4 haloalkyl" is mean to include
trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,
3-bromopropyl, and the like.
[0031] As used herein, the term "aryl" or "aromatic ring" means,
unless otherwise stated, a polyunsaturated, typically aromatic,
hydrocarbon group which can be a single ring or multiple rings (up
to three rings) which are fused together or linked covalently.
Similarly, the terms "heteroaryl" and "heteroaromatic ring" refer
to aryl groups (or rings) that contain from one to five heteroatoms
selected from N, O, and S, wherein the nitrogen and sulfur atoms
are optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. A heteroaryl group or heteroaromatic ring can be
attached to the remainder of the molecule through a heteroatom.
Non-limiting examples of aryl groups include phenyl, naphthyl and
biphenyl, while non-limiting examples of heteroaryl groups include
pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,
quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,
benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,
benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl,
indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl,
benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl,
isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,
pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for
each of the above noted aryl and heteroaryl ring systems are
selected from the group of acceptable substituents described
below.
[0032] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0033] As used herein the term "oxo" refers to a double bonded
oxygen (.dbd.O).
[0034] As used herein, the term "pharmaceutically acceptable salts"
is meant to include salts of the active compounds which are
prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the present disclosure contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present disclosure contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, S. M., et al,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66, 1-19). Certain specific compounds of the present disclosure
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0035] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present disclosure.
[0036] In addition to salt forms, the present disclosure provides
compounds which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present disclosure. Additionally, prodrugs can be converted to
the compounds of the present disclosure by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present disclosure when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0037] Certain compounds of the present disclosure can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the
present disclosure. Certain compounds of the present disclosure may
exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated by the
present disclosure and are intended to be within the scope of the
present disclosure.
[0038] Certain compounds of the present disclosure possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers, regioisomers and
individual isomers (e.g., separate enantiomers) are all intended to
be encompassed within the scope of the present disclosure. When a
stereochemical depiction is shown, it is meant to refer the
compound in which one of the isomers is present and substantially
free of the other isomer. `Substantially free of` another isomer
indicates at least an 80/20 ratio of the two isomers, more
preferably 90/10, or 95/5 or more. In some embodiments, one of the
isomers will be present in an amount of at least 99%.
[0039] The compounds of the present disclosure may also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. Unnatural proportions of an
isotope may be defined as ranging from the amount found in nature
to an amount consisting of 100% of the atom in question. For
example, the compounds may incorporate radioactive isotopes, such
as for example tritium (3H), iodine-125 (.sup.125I) or carbon-14
(.sup.14C), or non-radioactive isotopes, such as deuterium
(.sup.2H) or carbon-13 (.sup.13C). Such isotopic variations can
provide additional utilities to those described elsewhere with this
application. For instance, isotopic variants of the compounds of
the disclosure may find additional utility, including but not
limited to, as diagnostic and/or imaging reagents, or as
cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic
variants of the compounds of the disclosure can have altered
pharmacokinetic and pharmacodynamic characteristics which can
contribute to enhanced safety, tolerability or efficacy during
treatment. All isotopic variations of the compounds of the present
disclosure, whether radioactive or not, are intended to be
encompassed within the scope of the present disclosure.
Substitution with heavier isotopes such as deuterium, i.e. .sup.2H,
may afford certain therapeutic advantages resulting from greater
metabolic stability. For example, in vivo half-life may increase or
dosage requirements may be reduced.
[0040] As used herein, the terms "subject", "patient" or
"individual" are used herein interchangeably to include a human or
animal. For example, the animal subject may be a mammal, a primate
(e.g., a monkey), a livestock animal (e.g., a horse, a cow, a
sheep, a pig, or a goat), a companion animal (e.g., a dog, a cat),
a laboratory test animal (e.g., a mouse, a rat, a guinea pig, a
bird), an animal of veterinary significance, or an animal of
economic significance.
[0041] As used herein, the term "urine albumin-to-creatinine ratio"
refers to the ratio of albumin to creatinine as measured in a
subject's urine sample (e.g. (urine albumin/urine creatinine). This
is a common measure used to determine kidney function, because when
the kidneys are functioning properly, little to no albumin is found
in the urine and creative is normally released into the urine at a
relatively constant rate.
[0042] As used herein, the term "therapeutically effective amount"
means the amount of the subject compound that will elicit the
biological or medical response of a cell, tissue, system, or
animal, such as a human, that is being sought by the researcher,
veterinarian, medical doctor or other treatment provider.
[0043] As used herein, the term "selective CCR2 antagonist" refers
to a highly discriminatory compound that inhibits normal CCR2
activity with little or no cross reactivity on non-targeted
proteins such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,
CCR10, FPRL2, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7,
C3aR, and/or C5aR. In some embodiments, "selective CCR2
antagonists" have an IC.sub.50 that is at least 10, 100, 500,
1,000, 5,000, 10,000 or more times lower than for that of proteins
such as CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10,
FPRL2, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR,
and/or C5aR when measured in the assay types described in Example 3
of this application. In some embodiments, "selective CCR2
antagonists" do not inhibit the activity of CCR1, CCR3, CCR4, CCR5,
CCR6, CCR7, CCR8, CCR9, CCR10, FPRL2, CXCR1, CXCR2, CXCR3, CXCR4,
CXCR5, CXCR6, CXCR7, C3aR, and/or C5aR at concentrations of 1 .mu.M
or below in assay types described in Example 3 of this application.
The above-mentioned proteins are considered to be "not inhibited"
when they maintain 100%, 99%, 95%, 90%, or 85% of their activity
under the referenced conditions with a selective CCR2
antagonist.
[0044] As used herein, the term "composition" as used herein is
intended to encompass a product comprising the specified
ingredients in the specified amounts, as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. By "pharmaceutically
acceptable" it is meant the carrier, diluent or excipient must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
III. Methods of Treating Focal Segmental Glomerulosclerosis
[0045] Provided method of treating focal segmental
glomerulosclerosis, said method comprising administering to a
subject in need thereof a therapeutically effective amount of a
CCR2 antagonist.
[0046] In some embodiments, the CCR2 antagonist is a compound of
Formula I
##STR00003##
or a pharmaceutically acceptable form thereof, wherein [0047]
R.sup.1 and R.sup.2 are each independently selected from the group
consisting of hydrogen, halogen, C.sub.1-8 alkyl, CN, or C.sub.1-8
haloalkyl, provided that at least one of R.sup.1 or R.sup.2 is
other than hydrogen; [0048] R.sup.5 is halogen or C.sub.1-8 alkyl;
[0049] R.sup.6 is hydrogen or C.sub.1-8 alkyl; [0050] X.sup.1 and
X.sup.2 are each independently is CR.sup.7, N, or NO; [0051]
X.sup.4 is N or NO; [0052] X.sup.3 is CR.sup.7; [0053] X.sup.6 and
X.sup.7 are each independently selected from CR.sup.7, N, and NO;
[0054] R.sup.7 is independently selected from the group consisting
of hydrogen, halogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, --CN, --NO.sub.2, --OR.sup.8, --OC(O)R.sup.8,
--CO.sub.2R.sup.8, --C(O)R.sup.8, --C(O)NR.sup.9R.sup.8,
--OC(O)NR.sup.9R.sup.8, --NR.sup.10C(O)R.sup.8,
--NR.sup.10C(O)NR.sup.9R.sup.8, --NR.sup.9R.sup.8,
--NR.sup.10CO.sub.2R.sup.8, --SR.sup.8, --S(O)R.sup.8,
--S(O).sub.2R.sup.8, --S(O).sub.2NR.sup.9R.sup.8,
--NR.sup.10S(O).sub.2R.sup.8, C.sub.6-10 aryl, 5- to 10-membered
heteroaryl and 3- to 10-membered heterocyclyl; [0055] each R.sup.8,
R.sup.9 and R.sup.10 is independently selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, aryl, or heteroaryl; or R.sup.9 and R.sup.8 or
R.sup.10 and R.sup.8, together with the atom(s) to which they are
attached, form a 5-, 6-, or 7-membered ring; [0056] R.sup.11 is
selected from the group consisting of hydrogen, C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10 aryl, 5- to
10-membered heteroaryl and 3- to 10-membered heterocycle.
[0057] In some embodiments, the compound of Formula I has the
structure of Formula II
##STR00004##
or a pharmaceutically acceptable form thereof.
[0058] In some embodiments of the compound of Formula II, [0059]
R.sup.1 and R.sup.2 are each independently selected from the group
consisting of halogen, C.sub.1-8 alkyl, or C.sub.1-8 haloalkyl,
provided that at least one of R.sup.1 or R.sup.2 is other than
hydrogen; [0060] R.sup.5 is halogen or C.sub.1-8 alkyl; [0061]
X.sup.2 is CR.sup.7 or N; [0062] R.sup.7 is independently selected
from the group consisting of hydrogen, halogen, C.sub.1-8 alkyl,
--CN, --NO.sub.2, --OR.sup.8, and --NR.sup.9R.sup.8; [0063]
R.sup.11 is hydrogen or C.sub.1-8 alkyl.
[0064] In some embodiments of the compound of Formula II, [0065]
R.sup.1 is halogen [0066] R.sup.2C.sub.1-8 haloalkyl; [0067]
R.sup.5 is C.sub.1-8 alkyl; [0068] X.sup.2 is CR.sup.7 or N; [0069]
R.sup.7 is independently selected from the group consisting of
hydrogen, halogen, C.sub.1-8 alkyl; [0070] R.sup.11 is hydrogen or
C.sub.1-8 alkyl.
[0071] In some embodiments of the compound of Formula II, [0072]
R.sup.1 is chloro [0073] R.sup.2 trifluoromethyl; [0074] R.sup.5 is
methyl; [0075] X.sup.2 is CR.sup.7 or N; [0076] R.sup.7 is
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-8 alkyl; [0077] R.sup.11 is hydrogen or C.sub.1-8
alkyl.
[0078] In some embodiments, the compound of Formula II has the
structure of Compound 1
##STR00005##
or a pharmaceutically acceptable form thereof.
[0079] In some embodiments, the compound of Formula II has the
structure of Compound 2
##STR00006##
or a pharmaceutically acceptable form thereof.
[0080] In some embodiments, the CCR2 antagonist is a selective CCR2
antagonist. Selective CCR2 antagonists are highly discriminatory
compounds that have little or no cross reactivity with other
chemokine receptors. In some embodiments, selective CCR2
antagonists have an IC.sub.50 that is at least 10, 100, 500, 1,000,
5,000, 10,000 or more times lower than for that of proteins such as
CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, FPRL2,
CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR, and/or C5aR
when measured in the assay types described in Example 3 of this
application. In some embodiments, selective CCR2 antagonists do not
inhibit the activity of CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8,
CCR9, CCR10, FPRL2, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6,
CXCR7, C3aR, and/or C5aR at concentrations of 1 .mu.M or below in
assay types described in Example 3 of this application. The
above-mentioned proteins are considered to be "not inhibited" when
they maintain 100%, 99%, 95%, 90%, or 85% of their activity under
the referenced conditions with a selective CCR2 antagonist. In some
embodiments, the above-mentioned proteins maintain 100% of their
activity under the referenced conditions with a selective CCR2
antagonist. In some embodiments, the above-mentioned proteins
maintain 99% of their activity under the referenced conditions with
a selective CCR2 antagonist. In some embodiments, the
above-mentioned proteins maintain 95% of their activity under the
referenced conditions with a selective CCR2 antagonist. In some
embodiments, the above-mentioned proteins maintain 90% of their
activity under the referenced conditions with a selective CCR2
antagonist. In some embodiments, the above-mentioned proteins
maintain 85% of their activity under the referenced conditions with
a selective CCR2 antagonist.
[0081] Individuals with normal kidney function have little or no
albumin in the urine. On the other hand, creatinine is normally
released into the urine at a constant rate. Thus, the albumin to
creatinine ration in a subject's urine can be used as a metric of
kidney function. Accordingly, in some embodiments, administration
of the CCR2 antagonist to the subject in need thereof reduces a
urine albumin-to-creatinine ratio in said subject.
[0082] In some embodiments, the urine albumin-to-creatinine ratio
in said subject is reduced by at least 20% after 3 weeks of
administering the CCR2 antagonist. In some embodiments, the urine
albumin-to-creatinine ratio in said subject is reduced by at least
30% after 3 weeks of administering the CCR2 antagonist. In some
embodiments, the urine albumin-to-creatinine ratio in said subject
is reduced by at least 40% after 3 weeks of administering the CCR2
antagonist. In some embodiments, the urine albumin-to-creatinine
ratio in said subject is reduced by at least 50% after 3 weeks of
administering the CCR2 antagonist. In some embodiments, the urine
albumin-to-creatinine ratio in said subject is reduced by at least
60% after 3 weeks of administering the CCR2 antagonist
[0083] In the treatment or prevention of focal segmental
glomerulosclerosis an appropriate dosage level will generally be
about 0.001 to 100 mg per kg patient body weight per day which can
be administered in single or multiple doses. Preferably, the dosage
level will be about 0.01 to about 25 mg/kg per day; more preferably
about 0.05 to about 10 mg/kg per day. A suitable dosage level may
be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day,
or about 0.1 to 5 mg/kg per day. Within this range the dosage may
be 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per
day. For oral administration, the compositions are preferably
provided in the form of tablets containing 1.0 to 1000 milligrams
of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0,
25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,
600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. The compounds may be administered on a
regimen of 1 to 4 times per day, preferably once or twice per day.
In some embodiments, the CCR2 antagonist is administered daily.
[0084] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, hereditary
characteristics, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
IV. Combination Therapy
[0085] In some embodiments, methods of treating focal segmental
glomerulosclerosis include administering the CCR2 antagonists
described herein as part of combination therapy.
[0086] In some embodiments, the additional therapeutic agent is a
Renin-angiotensin-aldosterone (RAAS) blocker. In some embodiments,
the additional therapeutic agent is an endothelin receptor
antagonist. In some embodiments, the additional therapeutic agent
is a Renin-angiotensin-aldosterone (RAAS) blocker, and an
endothelin receptor antagonist.
[0087] RAAS blockers include Renin inhibitors, ACE inhibitors, and
angiotensin receptor blockers. As such, in some embodiments, the
RAAS blocker is a renin inhibitor. In some embodiments, the RAAS
blocker is an ACE inhibitor. In some embodiments, the RAAS blocker
is an angiotensin receptor blocker (ARB).
[0088] In some embodiments, the renin inhibitor is selected from
the group consisting of aliskiren, remikiren, H-142, SPP635,
SPP1148, SPP676, SPP1234, or combinations thereof.
[0089] In some embodiments, the ACE inhibitor is selected from the
group consisting of benazepril (tradename Lotensin.RTM.), captopril
(tradename Capoten.RTM.), enalapril (tradename Vasotec.RTM.),
fosinopril (tradename Monopril.RTM.), lisinopril (tradename
Prinivil.RTM., Zestril.RTM.), perindopril (tradename Aceon.RTM.),
quinapril (tradename Accupril.RTM.), rampipril (tradename
Altace.RTM.), trandolapril (tradename (Mavik.RTM.), or combinations
thereof.
[0090] In some embodiments, the angiotensin receptor blocker (ARB)
is selected from the group consisting of eprosartan (tradename
Teveten.RTM.), candesartan (tradename Atacand.RTM.), irbesartan
(tradename Avapro.RTM.), losartan (tradename Cozaar.RTM.),
olmesartan (tradename Benicar.RTM.), telmisartan (tradename
Micardis.RTM.), valsartan (tradename Diovan.RTM.), CGP-42112A,
DuP753, saralasin, sarthran, or combinations thereof. In some
embodiments, the angiotensin receptor blocker (ARB) is selected
from the group consisting of sparsentan, eprosartan (tradename
Teveten.RTM.), candesartan (tradename Atacand.RTM.), irbesartan
(tradename Avapro.RTM.), losartan (tradename Cozaar.RTM.),
olmesartan (tradename Benicar.RTM.), telmisartan (tradename
Micardis.RTM.), valsartan (tradename Diovan.RTM.), CGP-42112A,
DuP753, saralasin, sarthran, or combinations thereof. In some
embodiments, the angiotensin receptor blocker (ARB) is sparsentan.
A person of skill in the art will recognized that spartsentan is a
dual-acting receptor antagonist for endothelin (A type) receptors
and angiotensin II receptors.
[0091] In some embodiments, the endothelin receptor antagonist is
selected from the group consisting of sparsentan, bosentan,
macitentan, ambrisentan, sitazentan, aprocitentan, and artasentan.
In some embodiments, the endothelin receptor antagonist is selected
from the group consisting of bosentan, macitentan, ambrisentan,
sitazentan, aprocitentan, and artasentan. In some embodiments, the
endothelin receptor antagonist is sparsentan. A person of skill in
the art will recognized that spartsentan is a dual-acting receptor
antagonist for endothelin (A type) receptors and angiotensin II
receptors.
[0092] In some embodiments, the amount of additional therapeutic
agent is sub-therapeutic when the administered alone. Those of
skill in the art will appreciate that "combinations" can involve
combinations in treatments (i.e., two or more drugs can be
administered as a mixture, or at least concurrently or at least
introduced into a subject at different times but such that both are
in the bloodstream of a subject at the same time). Additionally,
compositions of the current disclosure may be administered prior to
or subsequent to a second therapeutic regimen.
[0093] The weight ratio of the CCR2 antagonists of the present
disclosure to the second active ingredient may be varied and will
depend upon the effective dose of each ingredient. Generally, an
effective dose of each will be used.
V. Pharmaceutical Compositions
[0094] The pharmaceutical compositions for the administration of
the compounds of this disclosure may conveniently be presented in
unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy. All methods include the step of
bringing the active ingredient into association with the carrier
which constitutes one or more accessory ingredients. In general,
the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In
the pharmaceutical composition the active object compound is
included in an amount sufficient to produce the desired effect.
[0095] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions and self-emulsifications
as described in U.S. Pat. No. 6,451,339, hard or soft capsules, or
syrups or elixirs. Compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions. Such compositions may
contain one or more agents selected from sweetening agents,
flavoring agents, coloring agents and preserving agents in order to
provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in admixture with other
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for
example, inert diluents such as cellulose, silicon dioxide,
aluminum oxide, calcium carbonate, sodium carbonate, glucose,
mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example PVP, cellulose, PEG,
starch, gelatin or acacia, and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated enterically or otherwise by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the techniques described in the U.S. Pat.
Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form
osmotic therapeutic tablets for control release.
[0096] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil. Additionally, emulsions can be
prepared with a non-water miscible ingredient such as oils and
stabilized with surfactants such as mono-diglycerides, PEG esters
and the like.
[0097] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0098] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0099] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0100] The pharmaceutical compositions of the disclosure may also
be in the form of oil in water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0101] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, and
flavoring and coloring agents. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0102] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, axed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0103] The compounds of the present disclosure may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols. Additionally, the
compounds can be administered via ocular delivery by means of
solutions or ointments. Still further, transdermal delivery of the
subject compounds can be accomplished by means of iontophoretic
patches and the like.
[0104] For topical use, creams, ointments, jellies, solutions or
suspensions containing the compounds of the present disclosure are
employed. As used herein, topical application is also meant to
include the use of mouth washes and gargles.
[0105] The pharmaceutical compositions and methods of the present
disclosure may further comprise other therapeutically active
compounds as noted herein, such as those applied in the treatment
of the above mentioned pathological conditions.
[0106] In one embodiment, the present disclosure provides a
composition consisting of a pharmaceutically acceptable carrier and
a compound of the disclosure.
VI. Kits
[0107] Also provided herein are kits comprising pharmaceutical
compositions of the compound of Formula I or the compound of
Formula II, and including kits for combination therapy.
[0108] In some aspects, the present invention provides a kit that
includes the compound of Formula II or the compound of Formula II.
Some of the kits described herein include a label describing a
method of administering the compound of Formula I or the compound
of Formula II. Some of the kits described herein include a label
describing a method of administering the compound of Formula I or
the compound of Formula II in combination with one or more (e.g.,
one, two three, one to two, or one to three) additional therapeutic
agents. Some of the kits described herein include a label
describing a method of treating focal segmental glomerulosclerosis.
In some embodiments, the kits described herein include a label
describing a method of reducing urine albumin excretion.
[0109] The compositions of the present invention, including but not
limited to, compositions comprising Compound 1 and or Compound 2 in
a bottle, jar, vial, ampoule, tube, or other container-closure
system approved by the United States Food and Drug Administration
(FDA) or other regulatory body, which may provide one or more
dosages containing the compounds. The package or dispenser may also
be accompanied by a notice associated with the container in a form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, the notice indicating approval by
the agency. In certain aspects, the kit may include a formulation
or composition as described herein, a container closure system
including the formulation or a dosage unit form including the
formulation, and a notice or instructions describing a method of
use as described herein.
EXAMPLES
[0110] The following examples are offered for illustrative
purposes, and are not intended to limit the invention in any
manner. Those of skill in the art will readily recognize a variety
of noncritical parameters which can be changed or modified to yield
essentially the same results.
Materials & Methods
Cells and Reagents
[0111] WEHI-274.1 and ThP1 cells were from ATCC (Rockville, Md.).
Human monocytes and neutrophils were isolated from healthy
volunteers (Stanford Blood Center, Palo Alto, Calif.) using MACS
separation reagents (Miltenyi, Germany). The CCR2 antagonist
Compound 1 was discovered and synthesized at ChemoCentryx and
stored as a dry powder until the time of formulation for in vivo
use. The compound was formulated in 1% hydroxylpropyl
methylcellulose (HPMC) (Sigma-Aldrich, St Louis, Mo.) in water for
subcutaneous (s.c.) injection at the indicated concentration.
Candesartan (AK Scientific, Union City, Calif.) and its vehicle
were dosed orally once daily at 5 mg/kg in water. Recombinant
chemokines were acquired from R&D Systems (Minneapolis, Minn.).
[125I]-CCL2 was from PerkinElmer (Boston, Mass.). Human plasma and
mouse plasma were from Bioreclamation (Hicksville, N.Y.)
Mice
[0112] Balb/c, 129s and 129X1/SvJ mice were purchased from Jackson
Laboratories (Bar Harbor, Me.) and housed at the ChemoCentryx
animal facility in accordance with guidelines described in the
Guide and Use of Laboratory Animals of the National Research
Council. All studies were approved by the ChemoCentryx
Institutional Animal Care and Use Committee. All animal studies
were conducted under the protocol entitled "Kidney Disease and
Diabetes Models in Mice", number CCX176-2008.
Mouse Pharmacokinetic (PK) Study
[0113] Compound 1 was formulated in 1% HPMC in water at 6 and 18
mg/mL concentrations, respectively. Five male 129s mice per dose
group were injected s.c. with 30 and 90 mg/kg of Compound 1. Blood
was drawn at 0.5, 2, 5, 4, 8, 12, and 24 hours post-dosing.
Compound 1 drug level was analyzed by LC-MS/MS at ChemoCentryx with
plasma samples.
Adriamycin Induced FSGS Model
[0114] These experiments were performed using female Balb/c mice
(Jackson Laboratories, Bar Harbor, Me.). The mice were kept on
standard chow and had free access to water. At age of 10 weeks, 7.5
mg/kg Adriamycin (Selleck Chemicals, Houston, Tex.) or saline
(control) was injected via tail vein in isoflurane-anesthetized
animals (day 0). Compound 1 and/or vehicle were dosed
subcutaneously once daily at 90 mg/kg formulated in 1% HPMC. The
RAAS blocker Candesartan (AK Scientific, Union City, Calif.) and
its vehicle were dosed orally once daily at 5 mg/kg, formulated in
water. All dosing started 2 hours prior Adriamycin challenge. The
mice were housed individually in metabolic cages for quantitative
collection of urinary albumin and creatinine.
5/6 Nephrectomy Model
[0115] 5/6 nephrectomy mice on the 129X1/SvJ background were
obtained from Jackson Laboratories, and were received at
ChemoCentryx after the surgery was performed at JAX. Under
isoflurane anesthesia, two-thirds of the left kidney mass was
removed at 5-6 weeks of age. Then, after 7 to 10 days, a right
unilateral nephrectomy was performed. The mice were fed a standard
chow and had free access to water. Three weeks after the 5/6
nephrectomy, the mice were grouped to ensure a similar starting
UAER in each treatment group. Compound 1 or its vehicle were dosed
subcutaneously once daily formulated in 1% HPMC. The RAAS blocker
candesartan (AK Scientific, Union City, Calif.) and its vehicle
were dosed orally once daily at 5 mg/kg formulated in water.
Sparsentan, the dual-acting receptor antagonist for endothelin (A
type) and angiotensin II receptors (Type 1) (Murugesan et al, 2005)
was synthesized at ChemoCentryx and was dosed orally twice daily at
90 mg/kg formulated in 1% HPMC. The mice were housed individually
in metabolic cages for quantitative collection of urinary albumin
and creatinine.
In Vitro Experiments
[0116] Chemotaxis, calcium mobilization, and radio-ligand binding
assays were conducted as previously described (Sullivan et al,
2013; Walters et al, 2010). Inhibition values (IC.sub.50) were
calculated using non-linear regression with a one-site competition
model (GraphPad Prism, GraphPad Software, La Jolla, Calif.). A2
values for assessment of potency in chemotaxis assays denotes the
concentration of the antagonist required to right-shift by 2-fold
the chemokine dose-response curve. Receptor engagement indices
(REIs) were calculated by dividing the plasma concentration of
Compound 1 by the measured potency in the chemotaxis assay in 100%
mouse serum. Urinary albumin was measured by ELISA (Bethyl Labs,
Montgomery, Tex.). Urinary and serum creatinine was measured by
LC-MS/MS at ChemoCentryx. The urinary albumin excretion rate (UAER)
was calculated as micrograms per 24 h. Blood urea nitrogen (BUN)
was measured by Antech Diagnostics (Morrisville, N.C.). The albumin
to creatinine ratio (ACR) was calculated as micrograms of albumin
per milligram of creatinine.
Histology
[0117] The kidneys were collected, fixed in formalin, embedded in
paraffin, and cut into 5-.mu.m-thick sections. Sections were
stained with Haematoxylin and Eosin (H&E) (Sigma-Aldrich, St
Louis, Mo.) and PAS (Periodic Acid Schiff) (Sigma-Aldrich, St
Louis, Mo.) and using standard protocols. Glomerular hypertrophy,
mesangial expansion, glomerular sclerosis, and tubular structure
were determined by examination of sections by an observer blinded
to the treatment groups.
Statistical Methods
[0118] Differences between treatment groups were analyzed using
Student's t-test.
Example 1: Inhibition of CCL2 Binding in WEHI-274 Murine Monocyte
Cell Line Using Compound 1
[0119] To determine if CCR2 plays a key role in FSGS we examined
the ability of Compound 1 to block radio-labeled CCR2 ligand, mJE
(CCL2) binding in the WEHI-274 murine monocyte cell line that
endogenously expresses CCR2. As shown in FIG. 1, Compound 1
inhibited mJE binding in WEHI 274 cells with an IC.sub.50 of 270
nM.
Example 2: Pharmacokinetics of Compound 1 in Mice
[0120] To determine if Compound 1 was suitable for in vivo
experiments, we analyzed its pharmacokinetic profile in mice. As
shown in FIG. 2, a single s.c. injection of Compound 1 at 90 mg/kg
provided a consistent level of Compound 1 in the blood, with a
concentration of approximately 3.5 .mu.M, 24 hours post-dosing. We
therefore concluded that a once daily s.c. administration of
Compound 1 would provide more than adequate CCR2 coverage.
Example 3: Selectivity of Compound 1 Inhibition
[0121] To determine the selectivity of Compound 1, we performed a
variety of binding-competition and functional assays on cell lines
that either endogenously expressed certain chemokine receptors, or
were individually transfected with various receptors for other
chemokines or chemotactic complement fragments. As summarized in
Table 1, Compound 1 did not inhibit any activity in a diverse
selection of other receptors even at concentrations well above one
micromolar.
TABLE-US-00001 TABLE 1 Selectivity Data for Compound 1 on Diverse
Family of Human Chemokine and Chemoattractant Receptors Compound 1
Receptor Assay Type Potency [nM] CCR2 ThPl Cell Chemotaxis 0.5 CCRI
Monocyte Chemotaxis >10,000 CCR3 293-CCR3 Calcium Mobilization
>10,000 CCR4 Activated Lymphocyte Calcium >10,000
Mobilization CCR5 L1.2-CCR5 Chemotaxis >8,000 CCR6 Activated
Lymphocyte Calcium >8,000 Mobilization CCR7 Activated Lymphocyte
Calcium >10,000 Mobilization CCR8 293-CCR8 Calcium Mobilization
>10,000 CCR9 Molt4 Serum Chemotaxis >10,000 CCR10 293-CCR10
Calcium Mobilization >10,000 FPRL2 Neutrophil Calcium
Mobilization >10,000 CXCR1 Neutrophil Calcium Mobilization
>10,000 CXCR2 Neutrophil Calcium Mobilization >10,000 CXCR3
Activated Lymphocyte Calcium >10,000 Mobilization CXCR4
Activated Lymphocyte Calcium >10,000 Mobilization CXCR5
Baf3-CXCR5 Calcium Mobilization >10,000 CXCR6 Activated
Lymphocyte Buffer >10,000 Chemotaxis CXCR7 293-CXCR7
Radio-ligand Binding >10,000 C3aR Neutrophil Calcium
Mobilization >10,000 C5aR Neutrophil Calcium Mobilization
>10,000 Shown are the IC.sub.50 values for inhibition of the
specified responses.
Example 4: Adriamycin Induced FSGS Model
[0122] To evaluate the therapeutic potential of Compound 1 for
FSGS, an Adriamycin induced FSGS model was used. Adriamycin is an
oncolytic antibiotic that induces proteinuria and
glomerulosclerosis in rodents after a single infusion. Rapid
reduction in urinary albumin excretion rate (UAER) (mg/day) by
Compound 1 alone, or in combination with RAAS blockade in
Adriamycin nephropathy model is observed (FIG. 3). Compound 1 as a
single agent had achieved a marked reduction in urine
albumin-to-creatinine ratio (UACR) by two weeks after the
Adriamycin infusion. Adriamycin treated mice displayed significant
reduction in UAER in response to Compound 1 alone or in combination
with RAAS blockade Table 2). The level of protection was equal to
or better than that of RAAS blockade. Combined treatment with
Compound 1 and RAAS blocker achieved a statistically significant
decrease in UACR with respect to vehicle, accompanied by similar
improvements in serum creatinine and BUN levels (FIG. 3).
TABLE-US-00002 TABLE 2 Reduction in UAER (mg/day) by Compound 1
alone, or in combination with RAAS blockade in Adriamycin
nephropathy model Week 1 Week2 Vehicle 75.87 89.99 Compound 1
26.15, p = 0.06 24.19, p = 0.032 RAAS Blocker 39.46, p = 0.16 66.87
Compound 1 + RAAS Blocker 20.39, p = 0.027 23, p = 0.030
Example 5: 5/6 Nephrectomy Model
[0123] To corroborated the above findings, another FSGS model
mechanistically distinct from the Adriamycin approach was tested,
the 5/6 nephrectomy model. Beginning three weeks after the
completion of surgery, the mice were treated with Compound 1 or
RAAS blocker either alone or in combination. As above, renal
function was quantified by measuring the UACR, UAER serum
creatinine and BUN levels.
[0124] As a mono-therapy, Compound 1 markedly reduced UACR, which
was apparent one week after the start of treatment (FIG. 4). This
inhibition persisted throughout the four-week study, with
reductions of 72% and 57% at weeks three and four, respectively. As
expected, RAAS blockade also significantly decreased the UACR.
Notably, the addition of Compound 1 to the RAAS blockade achieved a
further, statistically significant reduction in UACR, an additive
effect consistent with two distinct mechanisms of action and
similar results were obtained for UAER (Table 4).
TABLE-US-00003 TABLE 3 Reduction in UAER (mg/day) by Compound 1
alone, or in combination with RAAS blockade in 5/6 nephrectomy
model RAAS blockade in 5/6 nephrectomy model Week 1 Week2 Week3
Vehicle 26.82 17.21 39.55 Compound 1 15.68, p = 0.30 6.72, p = 0.07
11.75, p = 0.001 RAAS Blocker 8.27, p = 0.03 3.62, p = 0.03 3.32, p
< 0.0001 Compound 1 + RAAS 2.04, p = 0.005 1.45, p = 0.009 1.68,
p < 0.0001 Blocker No Treatment 31.88 20.58 21.08 .sup.1
Compound 1,90 mg/kg .sup.2 RAAS Blocker, 5 mg/kg
TABLE-US-00004 TABLE 4 Reduction in UAER (mg/day) by combination of
Compound 1 with RAAS blockade comparing with ET1/AT2 dual inhibitor
in 5/6 nephrectomy model Week 1 Week 2 Week 4 Vehicle 20.7 23.8
23.3 Compound 1 7.1, p = 0.07 11.0, p = 0.1 2.8, p = 0.02 RAAS
Blocker 9.4, p = 0.27 7.7, p = 0.06 1.7, p = 0.02 Compound 1 + RAAS
Blocker 2.1, p = 0.012 1.95, p = 0.002 1.5, p = 0.001 ET1/AT2 Dual
Blocker 2.6, p = 0.036 1.5,p = 0.01 1.15, p = 0.001
[0125] Compound 1 was associated with marked reductions in both
creatinine and BUN with respect to vehicle control at the four-week
time point (FIG. 5). The degree to which Compound 1 monotherapy
reduced these parameters was greater or equal to that observed with
RAAS blockade alone.
Example 6: Histological Analysis of Kidneys from the 5/6
Nephrectomy Model
[0126] Fixed kidney sections were obtained from 5/6 nephrectomized
mice for pathology. The sections were stained and evaluated to
determine whether the Compound 1-mediated improvements in renal
function were associated with anatomical changes. As shown in FIG.
6 (100.times. magnification) reductions in tubular dilation and
hyaline deposits (with respect to vehicle control) were evident in
the kidney remnants from mice treated with Compound 1 alone or in
combination with RAAS blockade. At higher magnification
(400.times.), changes in the glomeruli were apparent, including
decreased glomerular sclerosis, mesangial expansion, hyaline
deposits and tubular collapse (FIG. 7).
Example 7: Comparing CCR2 Inhibition to Endothelin Receptor
Inhibition in the 5/6 Nephrectomy Model
[0127] Endothelin has also been implicated in FSGS, and recent
clinical trials have featured a dual-acting receptor antagonist for
endothelin (A type) and angiotensin II receptors (Type 1)
(Murugesan et al, 2005). We used the 5/6 nephrectomy model to
determine how Compound 1 compared to this antagonist in providing
renal protection in FSGS-like disease. The combination of Compound
1 and RAAS blockade was as effective as the combination of
endothelin receptor inhibition plus RAAS blockade, as determined by
both UACR and UAER (FIG. 8). Specifically, UACR was reduced by
administration of Compound 1 alone (64.8%) or RAAS blocker alone
(73.4%), at week one. Addition of the CCR2 antagonist to RAAS
blockade further reduced the UACR (92.7% reduction vs vehicle,
p=0.02; p<0.045 versus RAAS blockade alone), which was
comparable to the combination of endothelin receptor plus RAAS
blockade (93.5% reduction vs vehicle, p=0.019). These results
indicate that CCR2 inhibition and endothelin receptor inhibition
are equally effective when combined with RAAS blockade in this
model of FSGS.
[0128] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, one of skill in the art will appreciate that
certain changes and modifications may be practiced within the scope
of the appended claims. In addition, each reference provided herein
is incorporated by reference in its entirety to the same extent as
if each reference was individually incorporated by reference. Where
a conflict exists between the instant application and a reference
provided herein, the instant application shall dominate.
* * * * *