7TRB

CRYSTAL STRUCTURE OF FARNESOID X-ACTIVATED RECEPTOR COMPLEXED WITH COMPOUND-32 AKA (1S,3S)-N-({4-[5-(2-FLUOROPR OPAN-2-YL)-1,2,4-OXADIAZOL-3-YL]BICYCLO[2.2.2]OCTAN-1-YL}M ETHYL)-3-HYDROXY-N-[4'-(2-HYDROXYPROPAN-2-YL)-[1,1'-BIPHEN YL]-3-YL]-3-(TRIFLUOROMETHYL)CYCLOBUTANE-1-CARBOXAMIDE

Summary for 7TRB

• Entry DOI: 10.2210/pdb7trb/pdb
• Descriptor: Bile acid receptor, co-activator, (1s,3s)-N-({4-[5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl]bicyclo[2.2.2]octan-1-yl}methyl)-3-hydroxy-N-[4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl]-3-(trifluoromethyl)cyclobutane-1-carboxamide, ... (4 entities in total)
• Functional Keywords: nhr, fxr, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 63262.38

Authors

Khan, J.A.,Ruzanov, M. (deposition date: 2022-01-28, release date: 2022-06-29, Last modification date: 2023-10-18)

Primary citation

Nara, S.J.,Jogi, S.,Cheruku, S.,Kandhasamy, S.,Jaipuri, F.,Kathi, P.K.,Reddy, S.,Sarodaya, S.,Cook, E.M.,Wang, T.,Sitkoff, D.,Rossi, K.A.,Ruzanov, M.,Kiefer, S.E.,Khan, J.A.,Gao, M.,Reddy, S.,Sivaprasad Lvj, S.,Sane, R.,Mosure, K.,Zhuo, X.,Cao, G.G.,Ziegler, M.,Azzara, A.,Krupinski, J.,Soars, M.G.,Ellsworth, B.A.,Wacker, D.A.
Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.
J.Med.Chem., 65:8948-8960, 2022

PubMed 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 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 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 in the liver and ileum by FXR agonists in vivo. Compound 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.

PubMed: 35704802
DOI: 10.1021/acs.jmedchem.2c00165

Experimental method

X-RAY DIFFRACTION (2.15 Å)