2. Academic Validation
  3. Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

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

  • J Med Chem. 2022 Jul 14;65(13):8948-8960. doi: 10.1021/acs.jmedchem.2c00165.
Susheel J Nara 1,  Srinivas Jogi 1,  Srinivas Cheruku 1,  Sarkunam Kandhasamy 1,  Firoz Jaipuri 1,  Pavan Kalyan Kathi 1,  Subba Reddy 1,  Sanket Sarodaya 1,  Erica M Cook 2,  Tao Wang 2,  Doree Sitkoff 2,  Karen A Rossi 2,  Max Ruzanov 2,  Susan E Kiefer 2,  Javed A Khan 2,  Mian Gao 3,  Satyanarayana Reddy 1,  Sankara Sivaprasad Lvj 1,  Ramola Sane 4,  Kathy Mosure 4,  Xiaoliang Zhuo 4,  Gary G Cao 5,  Milinda Ziegler 5,  Anthony Azzara 5,  John Krupinski 5,  Matthew G Soars 4,  Bruce A Ellsworth 2,  Dean A Wacker 2
Affiliations

Affiliations

  • 1 Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • 2 Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 3 Discovery Biotherapeutics, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 4 Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 5 Discovery Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
PMID: 35704802 DOI: 10.1021/acs.jmedchem.2c00165
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.

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