Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

Abstract

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

“…In a recent preclinical study, the BMS-986339, a novel non-bile acid FXR agonist showed potent in vitro and in vivo activation of FXR, with anti-fibrotic efficacy and tissue-selective effects in vivo. The safety of this molecule, however, still requires to be adequately tested in humans [ 257 ].…”

Photophysical Behavior of Self‐Organizing Derivatives of 10‐ and 12‐Vertex p‐Carboranes, and their Bicyclo[2.2.2]octane and Benzene Analogues

“…No further attempts to optimize the preparation of 15C were made at this time. An alternative approach could involve bromination of 1,4‐diphenylbicyclo[2.2.2]octane [43] followed by conversion of the resulting 15C to 3’C with MeONa/CuBr in DMF, according to a procedure for a similar compound [44] …”

“…An alternative approach could involve bromination of 1,4-diphenylbicyclo[2.2.2]octane [43] followed by conversion of the resulting 15C to 3'C with MeONa/CuBr in DMF, according to a procedure for a similar compound. [44] The requisite 1,4-dibromobicyclo[2.2.2]octane ( 22) was prepared in 55 % from bicyclo[2.2.2]octane-1,4-diol [40] (23) using PBr 3 and polyphosphoric acid (PPA), according to a literature procedure. [45] A similar reaction involving HBr/H 2 SO 4 /ZnBr 2 [23] gave a mixture of mono-and dibromobicyclo[2.2.2]octane in about 1 : 1 ratio.…”

“…[23] (2C): Product was obtained from 1-(4-bromophenyl)-4-pentylbicyclo[2.2.2]octane [23] (9C, Hal = Br, 168 mg, 0.50 mmol): 1 H NMR (500 MHz, CDCl 3 ) δ 0.91 (t, J = 7.2 Hz, 3H), 1.11-1.16 (m, 2H), 1.18-1.28 (m, 4H), 1.28-1.37 (m, 2H), 1.49-1.54 (m, 6H), 1.82-1.87 (m, 6H), 7. 44 Preparation of 4-cyano-4"-pentylterphenyl [24b] (2D): Product was obtained from 4-iodo-4'-pentylbiphenyl [70] (9D, Hal = I, 175 mg, 0.50 mmol): 1 H NMR (500 MHz, CDCl 3 ) δ 0.92 (t, J = 6.8 Hz, 3H), 1. 33…”

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

“…[ 7 , 8 , 9 , 10 , 11 , 12 ]). The interesting feature of the 1,2,4-oxadiazole moiety from a medicinal chemistry viewpoint is its potential coverage of a broad spectrum of therapeutic areas, including oncology [ 13 , 14 , 15 ], immunology [ 16 ], neurology [ 17 , 18 , 19 , 20 ], infectious diseases [ 21 , 22 , 23 , 24 ], metabolism and endocrinology [ 25 , 26 , 27 , 28 ], urology [ 29 , 30 ], gastroenterology [ 31 ], cardiology [ 32 ], rheumatology [ 33 ], and respirology [ 34 ]. Such versatility of the 1,2,4-oxadiazole motif, in our opinion, is due to its recognition as the hydrolytically stable bioisostere of the amide and ester bonds [ 35 , 36 , 37 , 38 , 39 ].…”