U.S. patent application number 17/516957 was filed with the patent office on 2022-02-24 for synthetic methods.
The applicant listed for this patent is GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO.2) LIMITED. Invention is credited to Gregg BARCAN, Jiasheng Guo, Christopher W. Morgan, Gheorghe D. Roiban, Peter W. Sutton.
Application Number | 20220055999 17/516957 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-24 |
United States Patent
Application |
20220055999 |
Kind Code |
A1 |
BARCAN; Gregg ; et
al. |
February 24, 2022 |
SYNTHETIC METHODS
Abstract
Methods for the preparation of the following compound are
disclosed. ##STR00001## The compound can be incorporated into
pharmaceutical formulations, including tablets and such tablets can
be used for treating cholestatic liver diseases.
Inventors: |
BARCAN; Gregg;
(Collegeville, PA) ; Guo; Jiasheng; (Collegeville,
PA) ; Morgan; Christopher W.; (Collegeville, PA)
; Roiban; Gheorghe D.; (Stevenage, GB) ; Sutton;
Peter W.; (Stevenage, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO.2) LIMITED |
Brentford |
|
GB |
|
|
Appl. No.: |
17/516957 |
Filed: |
November 2, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16305439 |
Nov 29, 2018 |
11186558 |
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PCT/IB2017/053839 |
Jun 27, 2017 |
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17516957 |
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62411776 |
Oct 24, 2016 |
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62355016 |
Jun 27, 2016 |
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International
Class: |
C07D 281/10 20060101
C07D281/10; C07D 303/04 20060101 C07D303/04; C12P 17/02 20060101
C12P017/02 |
Claims
1. A tablet comprising the compound GSK2330672: ##STR00016##
wherein the compound has been prepared by a synthesis comprising
the step of preparation of intermediate A,
(R)-2-butyl-2-ethyloxirane ##STR00017## followed by conversion of
(R)-2-butyl-2-ethyloxirane through one or more steps to GSK2330672.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to improved synthetic methods
for certain compounds that are useful in the treatment and
prevention of metabolic disorders, including diabetes mellitus
(Type I and Type II), obesity, and for the prophylaxix and/or
treatment of a liver disease.
BACKGROUND OF THE INVENTION
[0002] Patent publication WO 2011/137,135 discloses, among other
compounds, the following IBAT inhibitor compound. This patent
publication also discloses methods of synthesis of the
compound.
##STR00002##
[0003] The preparation of the above compound is also disclosed in
J. Med. Chem, Vol 56, pp 5094-5114 (2013) and in J. Org. Chem., Vol
78, pp 12726-12734 (2013). This compound is also known as
GSK2330672 and sometimes abbreviated as GSK672.
[0004] This compound is in clinical trial for the prophylaxix
and/or treatment of a cholestatic liver disease and the associated
pruritis.
SUMMARY OF THE INVENTION
[0005] Briefly, in a first aspect, the present invention discloses
an improved synthesis of the compound
##STR00003##
[0006] comprising the step of preparation of intermediate A,
(R)-2-butyl-2-ethyloxirane
##STR00004##
[0007] Briefly, in a second aspect, the present invention discloses
an improved synthesis of the compound
##STR00005##
[0008] comprising the step of preparation of intermediate H
depicted below
##STR00006##
[0009] In another aspect the present invention provides a tablet
comprising the compound GSK2330672.
[0010] In another aspect the present invention provides a method
for treating a cholestatic liver disease and/or the associated
pruritis, comprising administration of the tablet of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Preferably, the first aspect of the invention as described
above, comprises the kinetic resolution of racemic
2-butyl-2-ethyloxirane using an epoxide hydrolase to afford
(R)-2-butyl-2-ethyloxirane (compound A). Epoxide hydrolases capable
of selectively hydrolyzing 2-butyl-2-methloxirane and other
geminally disubstituted epoxides are known in the literature (Bala,
N. and Chimni, S. S. Tetrahedron: Asymmetry 2010, 21, 2879.), but
on screening a random selection of eight epoxide hydrolases, we
were surprised to identify some hits that were capable of
selectively hydrolyzing either enantiomer of the more symmetrical
2-butyl-2-ethyloxirane substrate which has not previously been
reported. In particular, the epoxide hydrolase from Agromyces
mediolanus ZJB1202030ID: JX467176 was very effective, transforming
a 300 g/L of racemic epoxide in 15 h to afford the desired product
(R)-2-butyl-2-ethyloxirane in 20% isolated yield and greater than
98% ee (solution yield, 40%) following extractive workup and
subsequent purification by distillation under reduced pressure.
[0012] 2-butyl-2-ethyloxirane concentrations within the range of
300-330 g/L are rarely reported in the literature especially with
respect to wild type enzymes and suggests that the enzyme is
unusually active and stable. During optimisation experiments we
discovered that higher loadings of 2-butyl-2-ethyloxirane led to
decreased enantioselectivity, either affording product that does
not meet specification or resulting in substantial yield loss due
to the need to run the resolution to higher conversion. On the
other hand too low 2-butyl-2-ethyloxirane concentration lead to
high enantioselectivity but is unattractive to run on scale due to
the high reaction volume.
[0013] Other parameters were also shown to influence the enzyme
enantioselectivity/activity and were screened to identify the
process optimal conditions: temperature, buffer, mixing rate,
cosolvent influence (solvents tested: heptane, TBME, hexane,
diethyl ether, toluene); reaction vessel (test tubes, falcon tubes
15, 50 mL, shake flaks, controlled laboratory reactors), reaction
time.
[0014] The enzyme can be used in different forms: whole cells,
lyophilised unclarified lysate, immobilised or lyophilised
clarified lysate while the loading can be also reduced from 20%
down to 5-8% leading to a slower reaction but unchanged
enantioselectivity. Use of lyophilised clarified lysate has the
particular advantage over cell paste in that it is less problematic
and cheaper to store and transport and leads to easier downstream
processing. Lyophilised lysate is also cheaper than immobilised
enzyme which can sometimes be advantageous in negating the need to
recycle
[0015] Some variants of Agromyces mediolanus ZJB12020301D:
JX467176, that were reported to afford improved enantioselectivity
to towards epichlorohydrin (Xue, F.; Liu, Z.-Q.; Wan, N.-W.; Zhu
H.-Q. and Zheng, Y.-G. RSC Adv., 2015, 5, 31525.), were also
prepared and tested. One of these variants N240D gave higher
activity (up to 30% higher) and slightly higher enantioselectivity
than the wild-type enzyme.
[0016] Epoxide hydrolase from Agromyces mediolanus ZJB12020301D:
JX467176 is a member of the large .alpha./.beta.-hydrolase fold
family (Xue, F.; Liu, Z.-Q.; Zou, S.-P.; Wan, N.-W.; Zhu, W.-Y.;
Zhu, Q. and Zheng, Y.-G. Process Biochemistry 2014, 49 409-417).
This class of epoxide hydrolase, where all members contain very
similar 3D architecture, is well known to encompass a surprisingly
diverse sequence range (Widersten, M.; Gurell, A. and Lindberg, D.
Biochim. Biophys. Acta, 2010, 1800, 316). Given that a number of
enantioselective epoxide hydrolase enzymes were identified from the
small subset tested, it is obvious that a larger set of epoxide
hydrolases would yield hits that are as, if more more, selective
than the epoxide hydrolase from Agromyces mediolanus ZJB12020301D:
JX467176 that has been identified. Given the increased activity and
enantioselectivity of one of three variants of the epoxide
hydrolase from Agromyces mediolanus ZJB12020301D: JX467176, that
had been selected for epichlorohydrin resolution, it is also highly
likely that directed evolution towards 2-butyl-2-methloxirane would
yield further improved mutants.
[0017] Preferably, the first aspect of the invention as described
above, further comprises the step of reacting
(R)-2-butyl-2-ethyloxirane with 3-hydroxy-4-methoxythiophenol to
produce the intermediate C
##STR00007##
[0018] Preferably, the first aspect of the invention as described
above, further comprises the step of converting intermediate C to
the intermediate E shown below
##STR00008##
[0019] Preferably, the second aspect of the invention as described
above, further comprises the step of converting intermediate H to
intermediate I depicted below
##STR00009##
[0020] Preferably the tablet and method of treatment of this
invention comprise GSK2330672 prepared by a method of this
invention.
[0021] In one aspect, the tablet of this invention further
comprises filler, disintegrant, and lubricant. In one aspect the
tablet of this invention comprises from 20 to 200 mg of GSK2330672.
One example of a suitable tablet is a tablet comprising GSK2330672,
microcrystalline cellulose, and magnesium stearate.
[0022] An illustrative synthetic scheme of how to prepare the IBAT
inhibitor compound GSK672 is depicted in Scheme 1. Enzymatic
resolution of (+)-2-butyl-ethyloxirane with epoxide hydrolase gave
rise to (R)-2-butyl-ethyloxirane (A). Epoxide ring opening of
(R)-2-butyl-ethyloxirane with thiophenol (B) and subsequent
treatment of (R)-tertiary alcohol (C) with chloroacetonitrile under
acidic conditions gave chloroacetamide (D), which was then
converted to intermediate (E) by cleavage of the chloroacetamide
with thiourea. Benzoylation of intermediate (E) with triflic acid
and benzoyl chloride afforded intermediate (F). Cyclization of
intermediate (F) followed by diastereoselective sulfoxidation of
the sulfide to the chiral sulfoxide, subsequent imine reduction
with sodium borohydride or borane provided intermediate (I), which
was then converted to intermediate (J). Intermediate (J) was
converted to the target compound using the methods disclosed in
Patent publication WO 2011/137,135.
##STR00010## ##STR00011##
[0023] The present invention differs from the syntheses disclosed
in WO 2011/137,135, J. Med. Chem, 2013, 56, 5094, J. Org. Chem.
2013, 78, 12726 and WO 2016020785 in that intermediates E and J in
the present invention are prepared via new, stereoselective and
more cost-efficient syntheses.
Abbreviations
[0024] Bz Benzoyl [0025] TfOH Trifluoromethanesulfonic acid [0026]
BzCl Benzoyl chloride [0027] S-BINOL (S)-(-)-1,1'-Bi(2-naphthol)
[0028] Ti(OiPr)4 Titanium isopropoxide [0029] t-BuOOH tert-Butyl
hydroperoxide [0030] DCM Dichloromethane [0031] NaBH.sub.4 Sodium
borohydride [0032] MeOH Methanol [0033]
mCPBAmeta-Chloroperoxybenzoic acid [0034] TFA Trifluoroacetic acid
[0035] MTBE Methyl t-butyl ether
Intermediate A: (R)-2-butyl-2-ethyloxirane
##STR00012##
[0036] Note: 1 wt is defined as the weight of
(+)-2-butyl-2-ethyloxirane charged to the reactor in grams. All
other weights, volumes and equivalents given are calculated
relative to this FIGURE.
[0037] Lyopholized epoxide hydrolase enzyme from clarified lysate
(20 wt %) was charged to the reaction vessel. Potassium phosphate
buffer adjusted to pH 7.4 (100 mM, 1.4 vol) was then charged to the
same reaction vessel and the agitation adjusted. The reaction was
started by the addition of racemic 2-butyl-2-ethyloxirane (22.6 g,
176.3 mmol, 1 wt). The reaction mixture was stirred at 30.degree.
C. The reaction was monitored by chiral GC until the enantiomeric
excess (ee) of (R)-2-butyl-2-ethyloxirane reached a value
.gtoreq.95% (R) (typically conversion is around .gtoreq.62.+-.2%
over a 15 hr time period). The reaction was quenched by adding
ethyl acetate (2.4 vol). The resultant biphasic solution was then
filtered over Celite. Additional ethyl acetate (1.2 vol) was used
to wash the celite cake. The layers were then separated. The
aqueous layer was discarded. The organic layer was washed with
brine (1.2 vol). The organic layer was then concentrated by
distillation under reduced pressure to afford a neat mixture of the
desired epoxide (R)-2-butyl-2-ethyloxirane and diol by-product
(S)-2-ethylhexane-1,2-diol. The mixture was distilled at 90.degree.
C. and 20.+-.5 mbar to give the desired epoxide
(R)-2-butyl-2-ethyloxirane (4.58 g, 20% yield, 99.2% purity, 95%
ee). .sup.1H NMR (400 MHz, CDCl.sub.3) b 2.61 (d, J=4.9 Hz, 1H),
2.59 (d, J=4.9 Hz, 1H), 1.72-1.46 (m, 4H), 1.42-1.26 (m, 4H),
0.99-0.87 (m, 6H). .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 60.2,
52.2, 33.7, 27.0, 26.9, 22.9, 14.0, 8.9.
Intermediate E:
(R)-5-((2-amino-2-ethylhexyl)thio)-2-methoxyphenol
##STR00013##
[0039] Under nitrogen protection, a reaction vessel was charged
with 3-hydroxy-4-methoxythiophenol (564 mg, 3.61 mmol),
(R)-2-butyl-2-ethyloxirane (509 mg, 3.97 mmol) and EtOH (3.4 mL).
The mixture was treated with a solution of NaOH (318 mg, 7.94 mmol)
in water (2.3 mL). The mixture was stirred at ambient temperature
for 20 h. The mixture was treated with toluene (4 mL) and stirred
for 2 min. The layers were separated and the organic layer was
discarded. The aqueous layer was neutralized with 2N HCl and
extracted with toluene. The extract was washed successively with
saturated aqueous Na.sub.2CO.sub.3 solution and water, concentrated
in vacuo to give intermediate C as an oil. The oil intermediate C
was dissolved in chloroacetonitrile (5.5 mL) and HOAc (2 mL). The
mixture was cooled to 0.degree. C. H.sub.2SO.sub.4 (0.96 mL, 18.05
mmol, pre-diluted with 0.33 mL of water) was added at a rate
maintaining the temperature below 5.degree. C. After stirred at
below 10.degree. C. for 0.5 h, the reaction mixture was treated
with water, extracted with MTBE. The extract was washed with
saturated aqueous NaHCO.sub.3 and concentrated in vacuo to give
intermediate D as an oil. The oil intermediate D was then dissolved
in EOH (9.1 mL) and treated with HOAc (1.8 mL) and thiourea (0.412
g, 5.42 mmol). The mixture was heated at reflux until completion,
and then cooled to ambient temperature. The solids were removed by
filtration The filtrate was concentrated in vacuo to give an oil.
The oil was treated with EtOAc, washed successively with saturated
aqueous Na.sub.2CO.sub.3 solution and water, and then concentrated
in vacuo to give intermediate E (851 mg, 83% yield over 3 steps,
79% purity) as an oil. 425 mg of the intermediate E was further
purified by silica gel chromatography to give intermediate E (223
mg, 100% purity, 94.8% ee). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.94 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.4, 2.2 Hz, 1H), 6.67
(d, J=8.4 Hz, 1H), 5.23 (s, 1H), 3.78 (s, 3H), 2.87 (s, 2H),
1.46-1.28 (m, 4H), 1.25-1.05 (m, 4H), 0.81 (t, J=6.9 Hz, 3H), 0.76
(t, J=7.45 Hz, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) .delta.
146.0, 129.1, 122.9, 117.7, 111.2, 56.0, 54.8, 47.5, 38.6, 31.8,
25.8, 23.3, 14.1, 8.0.
Intermediate H: (1
S,3R)-3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3-dihydrobenzo[f][1,-
4]thiazepine 1-oxide
##STR00014##
[0041] (S)-(-)-1,1'-Bi(2-napthol) (387 mg, 1.353 mmol, 1 equiv) was
charged into a 15 mL RBF. A magnetic stirbar was added and the
flask was sealed with a septum and flushed with nitrogen for 10
minutes. Dichloromethane (5 ml, 10 vol) was added followed by the
dropwise addition of titanium tetraisopropoxide (0.200 mL, 0.677
mmol, 0.5 equiv), at which time a deep red color change was
observed. Water (49 .mu.L, 2.71 mmol, 2 equiv) was added and the
reaction was stirred for 15 minutes. The septum was removed and
intermediate G (500 mg, 1.353 mmol, 1 equiv) was added in one
portion. The septum was replaced and the reaction was stirred for
15 minutes, after which time tert-butyl hydroperoxide (5.0-6.0 M in
decane, 0.284 mL, -1.42 mmol, -1.05 equiv) was added dropwise. The
reaction was stirred at ambient temperature for 2.5 hours with
monitoring by fast HPLC, after which time another 27 .mu.L of
tert-butyl hydroperoxide was added. After another 1 h, the reaction
was deemed complete by fast HPLC and quenched by the addition of
sat. sodium sulfite (1 mL, 2 vol). The reaction was transferred to
a separatory funnel and diluted with a small amount of water and
dichloromethane. The organic layer was separated, dried over
magnesium sulfate, concentrated and directly purified by column
chromatography (gradient of 20-100% EtOAc in hexanes) to yield 419
mg of intermediate H as an orange solid in 90% PAR and 80% yield as
a single diastereomer. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.74 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.40 (m, 1H), 7.39-7.33 (m,
2H), 6.67 (s, 1H), 3.81 (d, J=12.4 Hz, 1H), 3.79 (s, 3H), 3.30 (d,
J=12.4 Hz, 1H), 2.07-1.84 (m, 2H), 1.24-0.94 (m, 9H), 0.74 (t,
J=6.6 Hz, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 163.4,
149.0, 148.9, 140.5, 135.7, 130.4, 129.1, 128.2, 123.2, 112.3,
109.1, 70.6, 60.7, 56.5, 38.2, 37.2, 25.4, 22.9, 13.9, 8.6.
Intermediate J:
(3R,5R)-3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydrobe-
nzo[f][1,4]thiazepine 1,1-dioxide
##STR00015##
[0043] Intermediate H (100 mg, 0.259 mmol) was dissolved in
dichloromethane (370 .mu.L, 3.7 vol) and then methanol (830 .mu.L,
8.3 vol) was added. The reaction was cooled in an ice bath and
sodium borohydride (11.8 mg, 1.2 equiv) was added in one portion.
Monitoring by fast HPLC showed the reaction to be complete within
10 minutes. The reaction was quenched by the addition of water (0.5
mL, 5 vol). The reaction was transferred to a separatory funnel and
diluted with a small amount of water and dichloromethane. The
organic phase was split and washed with sat. NaHCO.sub.3, brine and
then dried over magnesium sulfate and concentrated to give
intermediate 1. Intermediate I was dissolved in dichloromethane (1
mL, 1 vol). The reaction was cooled in an ice bath and
trifluoroacetic acid (21 .mu.L, 1.05 equiv) was added. The reaction
was stirred for 5 minutes and then mCPBA (77%, 64 mg, 1.1 equiv)
was added in one portion and the reaction was removed from the ice
bath. After 10 minutes, fast HPLC showed less than 5% PAR of
starting material The reaction was stirred for another 10 minutes
and then sat. NaHCO.sub.3 (2.5 mL, 2.5 vol) and 1M NaSO.sub.3 (2.5
mL, 2.5 vol) were added and the reaction was stirred for several
minutes. The reaction was diluted with water and dichloromethane
and the organic layer was separated and dried over magnesium
sulfate. The solution was concentrated and recrystallization
attempted from TBME to give material of low purity. The solids and
mother liquor were recombined and chromatographed (0-50% EtOAc in
hexanes) to give 44 mg of intermediate J, -97% PAR and 44% yield
over 2 steps. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.65 (s,
1H), 7.46-7.35 (m, 4H), 7.35-7.28 (m, 1H), 6.15 (s, 1H), 6.02 (s,
1H), 3.58 (s, 3H), 3.41 (d, J=14.9 Hz, 1H), 3.05 (d, J=14.9 Hz,
1H), 2.22-2.09 (m, 1H), 1.89-1.77 (m, 1H), 1.57-1.39 (m, 2H),
1.35-1.06 (m, 4H), 0.88 (t, J=7.4 Hz, 3H), 0.83 (t, J=6.9 Hz, 3H).
.sup.13C NMR (125 MHz, CDCl.sub.3) .delta. 149.6, 143.9, 142.3,
138.5, 132.5, 128.5, 127.8, 127.3, 114.5, 110.8, 63.9, 57.4, 55.8,
55.2, 34.1, 31.2, 25.3, 22.9, 14.1, 7.6.
Treatment of a Cholestatic Liver Disease
[0044] A clinical study was carried out to investigate the safety,
tolerability, and effect of repeat doses of GSK672 administration
in patients with primary biliary cholangitis (PBC) and symptoms of
pruritus. The results of this study have been summarized and
published on clintrials.gov
[0045] A phase 2 double-blind, randomised, placebo controlled,
crossover trial in PBC patients with pruritus was conducted at two
specialist PBC centres in the United Kingdom between March 2014 and
November 2015. Subjects received oral GSK672 (45 to 90 mg) and
placebo twice daily for 14 days in a crossover sequence.
[0046] The primary end point was safety [measured by clinical and
laboratory assessments and adverse events (AEs)] and tolerability.
Secondary end points were: i) changes in pruritus scores from
baseline measured using a 0 to 10 numerical rating scale (NRS)
completed twice daily and PBC-40 itch domain scores and 5-D itch
scale and ii) changes in serum levels of total bile acids (TBA) and
7alpha-hydroxy-4-cholesten-3-one (C4). Serum levels of individual
BA species, autotaxin (ATX) activity and FGF19 were measured at
baseline and at the end of each treatment period.
[0047] 21 patients (n=21, all Caucasians, 18 females, mean age
52.9.+-.10.5 years) completed the study and were analysed. 68% were
taking Ursodeoxycholic acid (UDCA) during the study period. No
serious AEs were reported. Frequency of any AE was 81% (17/21) each
during placebo and GSK672 periods. Diarrhoea (33% & 5%) and
headache (29% & 33%) were the most frequent AE associated with
GSK672 and placebo respectively. GSK672 demonstrated 71% response
rate and showed significant reduction in itch intensity as measured
by NRS [-1.58 (95% CI: -2.48 to -0.68)], PBC-40 itch domain [-0.59
(95% CI: -0.94 to -0.24)] and 5-D itch [-4.55 (95% CI: -6.60 to
-2.49)]. Baseline values of serum TBA levels (48.64.+-.68.77 .mu.M)
decreased after GSK672 treatment (25.15.+-.23.85 .mu.M, p=0.15) but
not after placebo (50.29.+-.55.96 .mu.M, p=0.93). GSK672
significantly reduced serum levels of taurocholate (3.47.+-.7.15
vs. 0.31.+-.0.74 .mu.M, p=0.0004), glycocholate (4.44.+-.7.43 vs.
0.9.+-.1.21 .mu.M, p=0.0013), and taurochenodeoxycholate
(3.68.+-.7.50 vs. 0.8.+-.1.46 .mu.M, p=0.002). Following GSK672,
serum ATX activity (8.25.+-.4.17 vs. 6.95.+-.2.62 nMol/ml/min,
p=0.006) and serum FGF19 levels (162.9.+-.107.5 vs. 50.66.+-.47.31
pg/mL, p<0.0001) were lower and serum levels of deoxycholate
(3.1.+-.0.55 vs. 3.39.+-.0.64 .mu.M, p=0.009) and C4
(13.13.+-.10.04 vs.35.2.+-.25.32 ng/ml, p=0.0006) were higher.
[0048] Study Conclusion
[0049] In summary, two weeks of oral twice daily GSK2330672 was
well tolerated and reduced itch intensity in a high proportion of
PBC patients with pruritus. The substantial reduction in serum
total and conjugated primary bile acids and FGF19 levels and
increase in serum C4 levels are consistent with the mechanism of
action of IBAT inhibition. These results support further
investigation of GSK2330672 as a potential treatment for
cholestatic pruritus.
[0050] In addition to the above PBC study, GSK2330672 has been
administered in other studies. GSK2330672 is an inhibitor of the
ileal bile acid transporter (IBAT) that was first administered to
humans in June 2011. It is being evaluated as a treatment for liver
disease associated with cholestasis. Previous development for
treatment of type 2 diabetes (T2D) was terminated after completion
of two Phase II studies in T2D subjects taking background
metformin. As of 3 Jun. 2016 preliminary results are available for
one Phase II repeat dose study conducted in subjects with pruritus
due to Primary Biliary Cholangitis (PBC). Overall data are
available from 132 subjects exposed to GSK2330672, including 59
healthy subjects, 52 T2D subjects, and 21 PBC pruritus subjects. Of
these, the maximum dose of 90 mg BID was administered to 51
subjects, including 6 healthy patients (1 day), 24 T2D patients (up
to 14 days), and 21 PBC pruritus subjects (up to 14 days).
[0051] Among these studies three non-fatal serious adverse events
(SAEs) were reported. One healthy subject experienced a bleeding
thrombosed external haemorrhoid after a single 30 mg dose. Among
T2D subjects, one experienced acute cholecystitis and one
experienced atrial flutter/fibrillation. No SAEs were reported from
the PBC pruritus subjects. No deaths or pregnancies were reported
from any study. Gastrointestinal symptoms related to the targeted
site of action were the most commonly reported adverse events (AEs)
associated with GSK2330672 and included diarrhea, abdominal pain
and bowel movement irregularity. Trace positive fecal occult blood
tests were also observed in a minority of participants, with no
clinical sequelae. There were no clinically significant patterns of
abnormal vital sign measurements, electrocardiogram (ECG) changes,
spirometry parameters or clinical laboratory findings observed in
healthy subjects, T2D patients, or PBC pruritus patients.
[0052] In summary, administration of the IBAT inhibitor,
GSK2330672, did not result in any findings during safety monitoring
that would preclude conduct of planned short-term clinical trials
in patient populations with T2D or primary biliary cholangitis.
However, the high frequency of diarrhea AEs among T2D subjects
taking metformin 850 mg BID contributed to the decision to
terminate development of this condition.
[0053] Because the pharmacological target of GSK2330672 is located
on the brush border of enterocytes in the intestinal lumen, the
molecule was designed to have low permeability and high polar
surface area to limit absorption into the portal or systemic
circulation. Blood samples were obtained at frequent intervals
after administration of GSK2330672 for assays of plasma drug
concentrations. The majority of measurements were below the lower
limit of quantification for the assay (LLQ=1 ng/mL). The highest
measurable concentration was 5.33 ng/ml obtained 2 hours post-dose
in 1 subject, confirming limited absorption into the systemic
circulation.
[0054] Oral administration of GSK2330672 at doses .gtoreq.10 mg
clearly inhibited the ileal bile acid transporter. For healthy
subjects, single doses in this range significantly increased fecal
bile acid excretion measured over the subsequent 48 hours. Repeated
doses suppressed both fasting and post-prandial bile acid
concentrations measured on Day 1 and Day 10 of dosing. The
anticipated adaptive response to inhibited bile acid reabsorption,
upregulation of hepatic bile acid synthesis, was estimated by
measuring serum concentrations of 7-alpha-hydroxy-4-cholesten-3-one
(C4). With repeated doses of GSK2330672, serum C4 concentrations
increased up to 10-fold after ten days of dosing.
[0055] For the T2D subjects who completed the full 7-day treatment
period with GSK2330672 added to metformin in Study 200185, repeated
doses of GSK2330672 increased on Day 3 from 45 to 90 mg BID
significantly decreased serum total bile acid concentrations and
increased C4 concentrations. Furthermore, GSK2330672 significantly
reduced plasma glucose and low-density lipoprotein cholesterol
(LDL-C) from baseline when compared with placebo. For glucose
weighted mean area under the curve for the 24 hours after the
morning dose [AUC(0-24 h)], the decrease was statistically
significant [least square mean difference from placebo (95%
confidence interval): -34.76 mg/dL (-54.67, -14.85)]. GSK2330672
elicited a 41.7% mean reduction in fasting LDL-C from baseline,
compared to a 3.5% mean increase in the same time period for the
placebo group. Fasting serum triglycerides were relatively stable
in the GSK2330672 group and on average decreased -16.0% in the
placebo group.
[0056] For T2D subjects who completed the 14-day treatment period
with GSK2330672 added to metformin in Study 201351, repeated doses
of GSK2330672 from 10 mg to 90 mg BID reduced circulating prandial
glucose concentrations at all doses compared to placebo and
sitagliptin over 14 hours post-dose. The circulating concentrations
of serum C4 were increased over 14 hours post-dose by GSK2330672 at
all doses compared to placebo and sitagliptin; while C4
concentrations for the 10 mg, 20 mg, 30 mg and 60 mg of GSK2330672
groups appear to have reached a plateau by Day 7, this was not the
case for the 90 mg group in which the Day 14 values were greater
than those at Day 7.
[0057] In a two-week dose-ranging study among T2D subjects,
GSK2330672 significantly reduced plasma glucose and low-density
lipoprotein cholesterol (LDL-C) from baseline when compared with
placebo or sitagliptin. Reductions in fasting plasma glucose were
greater in GSK2330672 30 mg, 60 mg, and 90 mg groups on Day 7 and
Day 14 compared to placebo and sitagliptin groups. For the 90 mg
BID group, a statistically significant reduction was observed for
glucose weighted mean area under the curve for the 24 hours after
the morning dose [AUC(0-24 h)]: least square mean difference from
placebo (95% confidence interval) was -34.76 (-54.67, -14.85)
mg/dL. The reduction in fasting plasma insulin was variable at Day
14 across the GSK2330672 doses with no dose-response, but the
greatest reduction was observed in the GSK2330672 90 mg group
compared to the placebo: (LS mean difference from placebo [95% Cl]:
-17.61 pmol/L [-33.73, -1.48]). Reductions in fasting serum apoB,
total cholesterol, direct LDL cholesterol and non-HDL cholesterol
concentrations from baseline were observed in all the GSK2330672
dose groups, compared to placebo and sitagliptin, with no apparent
dose-response. The greatest mean reduction was observed in the
GSK2330672 60 mg group (LS mean change from baseline (expressed as
a ratio) difference from placebo [95% Cl]: 0.74 (0.66, 0.82). There
was a trend for an increase in triglyceride concentrations in all
the GSK2330672 dose groups, and there were no clinically meaningful
changes in HDL cholesterol in any dose group.
[0058] In a randomized placebo controlled 14 day cross-over study
in 22 subjects with PBC pruritus (Study 117213), GSK2330672 at 90
mg BD resulted in a statistically significant decrease in pruritus
severity compared to placebo as evidenced by 3 different rating
scales (10 point numerical rating scale, 5D Itch Scale, and
PBC-40). Reduction of pruritus severity occurred within the first
week of GSK2330672, continued to decrease through 2 weeks of
treatment and returned towards baseline upon blinded switch to
placebo. Decreases in fatigue, sleep disturbance and overall
disability were also noted upon GSK2330672 administration compared
to placebo. Statistically significant target engagement by
GSK2330672 was demonstrated by approximately 50% decrease in
concentration of serum total bile acids, and 3 fold increase in
serum C-4. GSK2330672 was minimally absorbed as evidenced by
detection in isolated samples in a small portion of subjects (8 out
of 21). No GSK2330672-related metabolites were detected in plasma
or urine. Parent compound (GSK2330672) was the only drug related
material observed in the urine, and the concentration was low and
not observed in all subjects. GSK2330672 did not inhibit the
absorption of ursodeoxycholic acid (UDCA), although there was a
statistically significant reduction in the pharmacokinetics of the
UDCA conjugates, glycoursodeoxycholic acid (GUDCA) and
tauroursodeoxycholic acid (TUDCA). Of note, plasma concentrations
of TUDCA and GUDCA were still at levels associated with clinical
efficacy in published studies of UDCA therapy for PBC. Dilger K,
Hohenester S, Winkler Budenhofer U, Bastiaansen B, Schapp F, Rust
C, Beuers U. Effect of ursodeoxycholic acid on bile acid profiles
and intestinal detoxification machinery in primary biliary
cirrhosis and health. Journal of Hepatology. 2012; 57:133-40.
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