Literature DB >> 34531950

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

Joseph Carpenter1, Gang Wu1, Ying Wang1, Erica M Cook1, Tao Wang1, Doree Sitkoff1, Karen A Rossi1, Kathy Mosure1, Xiaoliang Zhuo1, Gary G Cao1, Milinda Ziegler1, Anthony V Azzara1, Jack Krupinski1, Matthew G Soars1, Bruce Alan Ellsworth1, Dean A Wacker1.   

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.
© 2021 American Chemical Society.

Entities:  

Year:  2021        PMID： 34531950      PMCID： PMC8436248          DOI： 10.1021/acsmedchemlett.1c00198

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.632


  22 in total

1.  Design and synthesis of bridged piperidine and piperazine isosteres.

Authors:  Gaëtan Maertens; Oscar M Saavedra; Vito Vece; Miguel A Vilchis Reyes; Sofiane Hocine; Esat Öney; Bertrand Goument; Olivier Mirguet; Arnaud Le Tiran; Philippe Gloanec; Stephen Hanessian
Journal:  Bioorg Med Chem Lett       Date:  2018-06-19       Impact factor: 2.823

2.  Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).

Authors:  David C Tully; Paul V Rucker; Donatella Chianelli; Jennifer Williams; Agnès Vidal; Phil B Alper; Daniel Mutnick; Badry Bursulaya; James Schmeits; Xiangdong Wu; Dingjiu Bao; Jocelyn Zoll; Young Kim; Todd Groessl; Peter McNamara; H Martin Seidel; Valentina Molteni; Bo Liu; Andrew Phimister; Sean B Joseph; Bryan Laffitte
Journal:  J Med Chem       Date:  2017-12-08       Impact factor: 7.446

Review 3.  Emerging drugs for the treatment of non-alcoholic steatohepatitis: a focused review of farnesoid X receptor agonists.

Authors:  Raj A Shah; Naim Alkhouri; Kris V Kowdley
Journal:  Expert Opin Emerg Drugs       Date:  2020-08-12       Impact factor: 4.191

4.  Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids.

Authors:  K S Bramlett; S Yao; T P Burris
Journal:  Mol Genet Metab       Date:  2000-12       Impact factor: 4.797

Review 5.  Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.

Authors:  Christian Gege; Olaf Kinzel; Christoph Steeneck; Andreas Schulz; Claus Kremoser
Journal:  Curr Top Med Chem       Date:  2014       Impact factor: 3.295

6.  Structural basis for bile acid binding and activation of the nuclear receptor FXR.

Authors:  Li-Zhi Mi; Srikripa Devarakonda; Joel M Harp; Qing Han; Roberto Pellicciari; Timothy M Willson; Sepideh Khorasanizadeh; Fraydoon Rastinejad
Journal:  Mol Cell       Date:  2003-04       Impact factor: 17.970

7.  The TGR5 receptor mediates bile acid-induced itch and analgesia.

Authors:  Farzad Alemi; Edwin Kwon; Daniel P Poole; TinaMarie Lieu; Victoria Lyo; Fiore Cattaruzza; Ferda Cevikbas; Martin Steinhoff; Romina Nassini; Serena Materazzi; Raquel Guerrero-Alba; Eduardo Valdez-Morales; Graeme S Cottrell; Kristina Schoonjans; Pierangelo Geppetti; Stephen J Vanner; Nigel W Bunnett; Carlos U Corvera
Journal:  J Clin Invest       Date:  2013-03-25       Impact factor: 14.808

8.  Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.

Authors:  Adwoa Akwabi-Ameyaw; Jonathan Y Bass; Richard D Caldwell; Justin A Caravella; Lihong Chen; Katrina L Creech; David N Deaton; Stacey A Jones; Istvan Kaldor; Yaping Liu; Kevin P Madauss; Harry B Marr; Robert B McFadyen; Aaron B Miller; Frank Navas; Derek J Parks; Paul K Spearing; Dan Todd; Shawn P Williams; G Bruce Wisely
Journal:  Bioorg Med Chem Lett       Date:  2008-06-28       Impact factor: 2.823

9.  Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.

Authors:  Jason A Holt; Guizhen Luo; Andrew N Billin; John Bisi; Y Yvette McNeill; Karen F Kozarsky; Mary Donahee; Da Yuan Wang; Traci A Mansfield; Steven A Kliewer; Bryan Goodwin; Stacey A Jones
Journal:  Genes Dev       Date:  2003-06-18       Impact factor: 11.361

10.  TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition.

Authors:  Min-Jin Kim; Sang-A Park; Chun Hwa Kim; So-Yeon Park; Jung-Shin Kim; Dae-Kee Kim; Jeong-Seok Nam; Yhun Yhong Sheen
Journal:  Cell Physiol Biochem       Date:  2016-02-05
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