Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

Article abstract of DOI:10.1021/acsmedchemlett.1c00198

Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.

Full text of DOI:10.1021/acsmedchemlett.1c00198

pubs.acs.org/acsmedchemlett
Letter
Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the
Treatment of Nonalcoholic Steatohepatitis
Joseph Carpenter, Gang Wu, Ying Wang, Erica M. Cook, Tao Wang, Doree Sitkoff, Karen A. Rossi,
Kathy Mosure, Xiaoliang Zhuo, Gary G. Cao, Milinda Ziegler, Anthony V. Azzara, Jack Krupinski,
Matthew G. Soars, Bruce Alan Ellsworth, and Dean A. Wacker*
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ABSTRACT: Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-
cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-
(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid
farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation
of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation
model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued
evaluation.
KEYWORDS: Farnesoid X receptor (FXR), Nonalcoholic steatohepatitis (NASH), Nuclear hormone receptor (NHR), FGF15, CYP7a1
,
spirocycle, azaspiro[3.5]nonene
s the prevalence of obesity continues to rise across the
world, comorbidities are taking their toll on society.
(cilofexor) have entered clinical trials for NASH and related
disorders.6,8−11 Through our efforts to identify novel potent
FXR agonists, we discovered a series of spirocyclic-containing
compounds of which 6-(2-(5-cyclopropyl-3-(3,5-dichloropyr-
idin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-
(trifluoromethyl)quinoline-2-carboxylic acid, compound 1
(BMS-986318), exhibited potent in vitro activation of FXR,
good ADME properties, and promising activity in an in vivo
target engagement and efficacy model. In this article, we
describe the structure activity relationships (SARs) that led to
compound 1 and provide early in vivo data that support further
investigation as a possible candidate for the treatment of
NASH.
A
Individuals with obesity are at increased risk of developing
nonalcoholic fatty liver disease (NAFLD), which is charac-
terized by the accumulation of fat in the liver. In nonalcoholic
steatohepatitis (NASH), the advanced form of NAFLD, excess
hepatic lipid accumulation is accompanied by inflammation
and hepatocyte ballooning, with or without fibrosis.1 Patients
with NASH can progress to advanced fibrosis and eventually
cirrhosis of the liver that causes patients’ quality of life and life
expectancy to be greatly reduced.
A characteristic of NASH is metabolic dysregulation that
affects bile acids and lipids. The farnesoid X receptor (FXR) is
known as the master regulator of bile acids and controls their
production, distribution, and metabolism. In patients with
NASH, the autocrine and paracrine FXR signaling in the liver
and ileum has been shown to be disrupted.2−4 Pharmacological
activation of FXR has received considerable attention as a
possible means to treat NASH through perturbation of this
central pathway as evidenced by a number of ongoing clinical
trials.5,6
The lead clinical compound in development for NASH,
obeticholic acid (OCA), is a synthetic FXR bile acid analog of
cholic acid, a naturally occurring ligand of FXR. OCA is
approved for the treatment of primary biliary cholangitis
(PBC) and has recently been evaluated in clinical trials for the
treatment of NASH. Phase II clinical trial data indicates
reductions in hepatic steatosis, inflammation, and ballooning
degeneration with varying amounts of pericellular fibrosis.7 In
addition to modified bile acid-like agonists of FXR, nonbile
acid agonists such as LJN452 (tropifexor) and GS9674
Despite promising preliminary clinical results for FXR
agonism for the treatment of NASH, there are concerns over
OCA’s relatively narrow therapeutic window with rare but
serious cases of hepatotoxicity reported in patients with
advanced liver disease.12 Incidence of drug-induced pruritus
has been hypothesized to derive from the off-target TGR5
activity of OCA, and the natural and synthetic bile acids can
represent challenging pharmacokinetic profiles owing to their
propensity for bioconjugation and enterohepatic circula-
tion.13−15 Isoxazole-containing, nonbile acid FXR agonists
Received: April 7, 2021
Accepted: July 30, 2021
https://doi.org/10.1021/acsmedchemlett.1c00198
© XXXX American Chemical Society
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
A

ACS Medicinal Chemistry Letters
pubs.acs.org/acsmedchemlett
Letter
Figure 1. Bile acid FXR agonist INT-747 (OCA) and isoxazole-containing nonbile acid FXR agonists.
Table 1. Exploration of Central Linker
a
Values represent the mean of three or more experiments.
B
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Letter
Table 2. Optimization of Azaspiro[3.5]nonene-Containing Compounds
a
Values are the mean of three or more experiments. NT = not tested.
offer the promise of increased receptor selectivity with
improved pharmacokinetic properties. To help guide the
discovery of nonbile acid FXR agonists, numerous X-ray crystal
structures are known in the isoxazole series of FXR agonists;
common to them is the conserved interaction of the isoxazole,
or related heteroaryl with FXR protein residue W469 and
H447, and an extended linker that directs a carboxylic acid or
surrogate toward R331.16−19 Despite the many modifications
reported within this class of FXR agonists, one portion of the
scaffold where little work has been reported is around the
highly conserved methylene ether linkage adjacent to the
isoxazole. Therefore, we sought to target this section of the
molecule to investigate its effects on ADME properties and
FXR potency (see Figure 1).
With the intent of modulating ADME properties while
maintaining FXR agonist potency, we specifically targeted the
methylene ether linkage as a potential site for modification and
differentiation from existing FXR ligands (Table 1). In order to
assess the potency of our newly synthesized compounds, we
employed an FXR Gal4 luciferase reporter system as our
primary assay, and the FXR steroid receptor coactivator 1
(SRC-1) recruitment assay for selected compounds of interest
(assay details included in the Supporting Information). SRC-1
is a transcriptional cofactor protein which binds to the FXR
ligand binding domain and plays a key role in the repression of
C
https://doi.org/10.1021/acsmedchemlett.1c00198
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pubs.acs.org/acsmedchemlett
Letter
CYP7A1 expression in the liver.20 One of our early leads was
the spirocyclic acetal (compound 2) which, despite its modest
potency in the FXR Gal-4 luciferase reporter assay (227 96
nM, as with all compounds described was a full agonist) and
poor chemical stability (prone to hydrolysis at low pH, data
not shown), opened the possibility of spirocycles being
tolerated as a replacement for the methylene ether, a discovery
that had no literature precedent to our knowledge. The related
ketal linker (compound 3) was also synthesized but was found
to have reduced potency relative to 2 (1359 105 nM). In a
simultaneous effort, we found that the ether oxygen in this
series could be replaced with carbon, and the ethylene-linked
compound 4 was found to serve as a suitable surrogate for the
Although the initial in vitro and in vivo data around
compound 8 was compelling, additional in vitro ADME
profiling revealed liabilities that prevented the advancement of
this compound for further investigation. In particular,
compound 8 exhibited inhibition of CYP3A4 (IC50 = 0.9 μM)
and CYP2C8 (IC50 = 6.9 μM). Given the frequent
comorbidities of the NASH patient population, there is a
high likelihood that patients may be taking other prescription
drugs, and we sought to avoid potential drug−drug
interactions (DDIs) that could occur through inhibition of
the metabolizing CYP enzymes. In addition to concerns over
CYP inhibition of 8, metabolite identification studies revealed
that a high percentage of bioactivation was possible in vivo as
measured through glutathione (GSH) adduct formation on the
2,6-dichlorophenyl ring.
methylene ether linkage (21.4
3.4 nM) albeit with lower
than desired metabolic stability in human liver microsomes
(HLM) (t1/2 = 19 min). In an attempt to rigidify and stabilize
the alkyl-based linker, we introduced unsaturation into the
system in the form of the E alkene (compound 5) which gave a
2-fold improvement in potency in the FXR Gal4 assay (10.5
5.1 nM) and demonstrated similar potency in its ability to
induce recruitment of the SRC-1 coactivator (23.3 2.4 nM).
Despite falling within our desired range of FXR potency,
compound 5 lacked the requisite microsomal metabolic
stability for advancement to further profiling (t1/2 = 13 min
in HLM). In an attempt to block potential oxidative
metabolism of the piperidine linker, we explored bicyclic
analogs that would hopefully improve metabolic stability while
maintaining potency.21 Among the analogs we explored, the
azabicyclo[3.2.1]octane analog 6 gave a modest improvement
in mouse liver microsomal (MLM) stability but no improve-
ment in HLM stability relative to piperidine 5. Moreover, the
modification resulted in complete loss of FXR agonist potency
(>20,000 nM). The azabicyclo[3.1.0]hexane analog 7 did
improve HLM and MLM stability but came with an ∼10-fold
loss in potency relative to 5 in the Gal4 FXR reporter assay and
an ∼30-fold loss of potency in the FXR SRC-1 recruitment
assay. A major breakthrough in our effort was discovered by
combining our findings of the spirocyclic and alkene linkers to
give the azaspiro[3.5]nonene 8 which maintained the desired
balance between FXR agonist potency and metabolic stability
(7.1 3.3 nM; t1/2 = 51 min). Reduction of the linker alkene
to give azaspiro[3.5]nonane 9 had a negative impact on
potency (202 184 nM).
Given their promising potency in the FXR Gal4 and SRC-1
recruitment assays, compounds 5 and 8 were evaluated in a
mouse pharmacokinetic/pharmacodynamic (PK/PD) study
wherein we could readily assess these compounds’ ability to
impact biomarkers that are indicative of in vivo FXR target
engagement. FXR is involved in paracrine and endocrine
signaling by inducing the production and secretion of the
hormone fibroblast growth factor 15 (FGF15), the mouse
ortholog of FGF19 in humans, which can contribute to the
regulation of bile acid concentrations.3,4 Another function of
FXR in the liver is regulation of the conversion of cholesterol
to bile acids by the rate-limiting enzyme cholesterol 7-alpha-
hydroxylase (CYP7A1). Therefore, proximal readouts for
activation of FXR in vivo can be monitored through changes
in Fgf15 and Cyp7a1 gene expression.3,4,6 Six hours following a
single 3 mg/kg dose of compound in mice, there was a 10-fold
increase of FGF15 and a 96% reduction of CYP7A1 mRNA for
5 and an 18-fold increase in FGF15 and a 99% reduction of
CYP7A1 for 8 relative to vehicle control (Table 3).
Having determined that the azaspiro[3.5]nonene linker
provided a suitable balance between FXR agonist potency and
metabolic stability, we explored optimization of other regions
of the molecule to improve the CYP inhibition and suppress
GSH adduct formation that was observed for 8 (Table 2). In
order to reduce the GSH adduct formation, we modified the
2,6-dichlorophenyl ring to reduce the electron density to
inhibit reactive intermediate formation. The 2-trifluoromethyl-
phenyl (compound 10) and 2-trifluoromethoxyphenyl (com-
pound 11) gave modest but acceptable reductions in FXR
agonist potency (13.8
6.4 nM and 49.5
15.3 nM,
respectively), but these analogs still suffered GSH adduct
metabolite formation. Introduction of a nitrogen into the
phenyl ring to give the 3,5-dichloropyridine-containing
compound 12 resulted in a 4-fold reduction in potency but
only slightly improved CYP inhibition and reduced, but did
not completely prevent, the extent of GSH adduct formation.
Simultaneous to our efforts to find a replacement for the 2,6-
dichlorophenyl ring that was not susceptible to GSH adduct
formation, we explored changes to the right-hand benzothia-
zole carboxylic acid. FXR agonist potency was somewhat
sensitive to changes in this region of the molecule as the
nicotinic acid isomer 13 retained moderate potency (30.5
8.9 nM), but the picolinic acid isomer 14 was over 10-fold less
potent (342 103 nM). While the nicotinic acid analog 13
was within a reasonable potency range, this compound gave no
clear advantage with respect to CYP inhibition or GSH adduct
formation. Indole 15, which is contained in the clinical
compound LY2562175, was also less potent than the
benzothiazole, exhibited CYP inhibition, and was prone to
GSH conjugation. Despite a nearly 10-fold reduction in
potency relative to 8, quinoline analog 16 gave a modestly
improved CYP profile and, although still observable, had a
reduced propensity for bioactivation and GSH conjugation. To
try to capitalize on reduced adduct formation, a quinolone acid
was combined with the less reactive 2,6-dichlorophenyl
replacements. We prepared the 2,6-dichloro-4-fluoro analog
17, but this modification came with an unsuitable reduction in
FXR agonist potency (Gal4 EC50 = 522 41 nM). Likewise,
the 3,5-dichloropyridyl analog 18 lacked the desired potency
but did completely suppress GSH conjugate formation by
eliminating oxidative metabolism of the dichlorophenyl ring. In
an attempt to regain potency, a strategic investigation around
the impact of substituents on the quinoline revealed that
substitution at the 4-position provided enhanced FXR agonist
potency. The 4-CF3 analog 1 was nearly 4-fold more potent
than 18 and only 2-fold less potent than the corresponding
benzothiazole analog 12 in both the Gal4 and SRC-1
D
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recruitment assays (53.1 26.3 nM and 350
respectively). Moreover, compound 1 was stable in both in
HLM and MLM (t1/2 of >120 min) and did not exhibit any
detectable formation of GSH solving several key issues in the
chemotype. The selectivity of compound 1 for FXR versus a
panel of NHRs was assessed, and the EC50s were all >40 μM
for all tested NHRs (RORγ, RORα, PPARα, PPARγ, PPARδ,
LXRα, LXRβ, AR, ER, GR, PR).
pubs.acs.org/acsmedchemlett
Letter
210 nM,
levels observed for the sham control group across all doses
tested (see Figure 2), while ALK5 inhibitors (SB525334) have
Determining the in vivo activity, 3 mg/kg of compound 1
was administered orally in mice, resulting in a 19-fold increase
in liver FGF15 and a 94% reduction of CYP7A1 in the PD assay
demonstrating its ability to affect these key markers of target
engagement (Table 3). It is interesting to note that despite the
Table 3. Response of Selected FXR Agonists in the Mouse
a
PK/PD Model
liver FGF15
CYP7a1
plasma exposure
at 6 h (nM)
compd
dose
(fold increase) (% reduction)
5
8
1
3 mg/kg
3 mg/kg
3 mg/kg
10×
18×
19×
−96%
−99%
−94%
195
387
37
Figure 2. Effects of compound 1 in the mouse bile duct ligation
model of liver cholestasis and fibrosis. #### p ≤ 0.0001 BDL-vehicle
group vs sham vehicle. **** p ≤ 0.0001 compound treatment groups
vs the BDL-vehicle group.
a
The compounds were administered as a solution in the following
vehicle: 5% ethanol; 90% PEG400; 5% TPGS.
demonstrated effects in the bile duct ligation model did not
give a significant reduction in hydroxyproline levels in our
studies.24 The robust reduction in hydroxyproline levels in this
study lends support for the antifibrotic potential of compound
1.
reduced in vitro potency and lower plasma exposure at 6 h of 1
relative to compounds 5 and 8, it is able to induce comparable
gene changes in the PD assay.
The pharmacokinetic profile of 1 was evaluated in C57B6
mice (Table 4). The compound exhibited low clearance that
The synthesis of 1 (see Scheme 1) commenced with the
condensation of 3,5-dichloroisonicotinaldehyde (1a) and
hydroxylamine hydrochloride in pyridine followed by chlori-
nation with NCS in DMF to give pyridinecarboximidoyl
chloride 1b. 1,3-Dipolar cycloaddition of 1b with cyclo-
propylacetylene generated the desired 3,5 substituted isoxazole
that was subsequently brominated selectively at the isoxazole
4-position with NBS in DMF to yield the trisubstituted
isoxazole 1f. The bromoisoxazole served as a key intermediate
for the synthesis of several final compounds. For the synthesis
of 1, n-BuLi was added to a solution of 1f in THF at −78 °C,
and after 10 min, a THF solution of commercially available
tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate was
added slowly to the cold mixture to give tertiary alcohol 1g.
Elimination of the tertiary hydroxyl and concomitant Boc
deprotection of the piperidine were accomplished with TFA in
DCM at room temperature, and following removal of the
residual TFA and other volatiles, the resulting piperdine TFA
salt was coupled to bromoquinoline 1k in good yield under
Buchwald-Hartwig conditions. The synthesis of bromoquino-
line 1k was carried out through the T3P-mediated con-
densation of 1i and 1j. The penultimate ethyl ester was
hydrolyzed with LiOH in a solvent mixture consisting of
10:4:1 THF:H2O:MeOH to afford 1. The optimized eight-step
process to deliver compound 1 could be carried out on a
multigram scale to deliver quantities of material that were
sufficient to supply the desired preclinical studies.
Table 4. Pharmacokinetic Profile of Compound 1 in C57B6
Mice
a
Cmax
AUC
t1/2
Vss
Cl
F
PPB Fu
(%)
dose
(nM) (nM·h) (h) (L/kg) mL/min/kg (%)
1 mg/kg
IV
1490
1220
1033
9317
6646
4759
2.6
2.3
2
0.56
3.8
<0.01
2 mg/kg
36
26
a
PO
2 mg/kg
susp.
b
PO
a
The compound was administered as a solution in the following
b
vehicle: 5% ethanol; 90% PEG400; 5% TPGS. The compound was
administered as a suspension in the following vehicle: = 0.5%
Methocel A4M; 0.1% Tween 80; 99.4% water.
was only 4% of mouse liver blood flow (3.8 mL/min/kg), with
reasonable bioavailability when administered orally as either a
solution or suspension. The compound has a low volume of
distribution and is highly bound by plasma proteins.
Given its in vitro profile, response in the PD assay, and
robust PK, compound 1 was selected for evaluation in a mouse
bile duct ligation (BDL) model of liver cholestasis and fibrosis.
It has been demonstrated that obstruction of the extrahepatic
biliary system initiates a cascade of events that leads to
inflammation and cholestasis culminating in a strong fibrotic
reaction and can serve to mimic the fibrotic component of
NASH. Increases in hydroxyproline in this model show a
strong correlation with the degree of fibrosis, and compounds
with the ability to reduce levels of hydroxyproline are
correlated with antifibrotic efficacy.22,23 In this model,
compound 1, administered to mice at 10, 30, and 100 mg/
kg, was able to reduce hydroxyproline in liver tissue to the
In summary, compound 1 exhibited potent in vitro FXR
agonist activity in both the FXR Gal4 reporter and SRC-1
recruitment assays. This novel spirocycle-containing FXR
agonist displayed a suitable pharmacokinetic profile as well
as robust in vivo FXR biomarker movement in a pharmacody-
namic target engagement assay. Compound 1 demonstrated in
vivo efficacy in the mouse bile duct ligation model of liver
E
https://doi.org/10.1021/acsmedchemlett.1c00198
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Letter
a
Scheme 1. Synthesis of 1
a
Reagents and conditions. (a) NH2OH·HCl, pyridine, 10 min, rt, 100%; (b) NCS, DMF, 16 h, 40 °C, 94%; (c) cyclopropylacetylene, Et3N, DCM,
14 h, 85%; (d) NBS, DMF, 36 h, 50 °C, 94%; (e) n-BuLi, THF, −78 °C, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate, 3 h, 67%; (f) TFA,
1 h, rt, 100%; (g) 1k, RuPhos Pd Gen II, Cs2CO3, dioxane 18 h, 90 °C, used crude; (h) LiOH·H2O, THF, MeOH, H2O, 2 h, 90 °C, 65%; (i) T3P/
EtOAc, DMF, 16 h, 65 °C, 87%.
cholestasis and fibrosis. The overall profile of 1 supports
further investigation of this compound as an antifibrotic
therapy.
Research Institute, Princeton, New Jersey 08543-5400,
United States; orcid.org/0000-0003-0885-1590
Gang Wu − Departments of Small Molecule Drug Discovery,
Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Ying Wang − Departments of Small Molecule Drug Discovery,
Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00198.
■
sı
Synthetic procedures, analytical data, in vitro assay
protocols, in vivo pharmacokinetic studies, and in vivo
efficacy model details (PDF)
Erica M. Cook − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Tao Wang − Departments of Small Molecule Drug Discovery,
Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States; orcid.org/0000-0002-5866-8148
Doree Sitkoff − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
AUTHOR INFORMATION
Corresponding Author
■
Dean A. Wacker − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400, United
States; orcid.org/0000-0002-6030-153X;
Email: dean.wacker@bms.com
Authors
Joseph Carpenter − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
F
https://doi.org/10.1021/acsmedchemlett.1c00198
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Letter
Research Institute, Princeton, New Jersey 08543-5400,
United States
Karen A. Rossi − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Kathy Mosure − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Xiaoliang Zhuo − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
TGR5, Takeda G protein-coupled bile acid receptor 5; SRC-1,
steroid receptor coactivator-1; HLM, human liver microsomes;
MLM, mouse liver microsomes; GSH, glutathione; ROR,
retinoic acid-related orphan receptors; LXR, liver X receptor;
AR, androgen receptor; ER, estrogen receptor; GR, glucocorti-
coid receptor; PR, progesterone receptor; NT, not tested; Cmax
,
maximum concentration; Vss, steady state volume of
distribution; Cl, clearance; Fu, fraction unbound; TPGS, D-α-
tocopherol polyethylene glycol succinate; veh, vehicle;
NH2OH·HCl, hydroxylamine hydrochloride; Et3N, triethyl-
amine; n-BuLi, n-butyllithium; RuPhos Pd Gen II, chloro(2-
dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2′-
amino-1,1′-biphenyl-2-yl)palladium(II); Cs2CO3, cesium car-
bonate; LiOH·H2O, lithium hydroxide monohydrate; MeOH,
methanol; H2O, water; T3P, propanephosphonic acid
anhydride; EtOAc, ethyl acetate
Gary G. Cao − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Milinda Ziegler − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Anthony V. Azzara − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Jack Krupinski − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Matthew G. Soars − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States
Bruce Alan Ellsworth − Departments of Small Molecule Drug
Discovery, Discovery Biology, and Pharmaceutical Candidate
Optimization, Bristol-Myers Squibb, Pharmaceutical
Research Institute, Princeton, New Jersey 08543-5400,
United States; orcid.org/0000-0002-2788-1819
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00198
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Sarah Traeger for
analytical support and Kevin Pyszka and Tatyana Zvyaga for
in vitro ADMET support in the preparation of this manuscript.
ABBREVIATIONS
■
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic
steatohepatitis; FXR, farnesoid X receptor; OCA, obeticholic
acid; PBC, primary biliary cholangitis; BDL, bile duct ligation;
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