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Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR Agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH)

Tully, David and Rucker, Paul and Chianelli, Donatella and Williams, Jennifer and Biggart, Agnes and Alper, Phillip and Schmeits, James and Zoll, Jocelyn and Kim, Young and Molteni, Valentina and Liu, Bo and Phimister, Andrew and Joseph, Sean and Laffitte, Bryan and Wu, Xiangdong and Mcnamara, Peter and Seidel, Martin and Mutnick, Daniel and Bursulaya, Badry and Bao, Dingjiu and Groessl, Todd (2017) Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR Agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). Journal of Medicinal Chemistry, 60 (24). pp. 9960-9973. ISSN 0022-26231520-4804

Abstract

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and non-alcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452) a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into Phase 2 human clinical trials in patients with NASH and PBC.

Item Type: Article
Date Deposited: 23 Jan 2018 00:45
Last Modified: 23 Jan 2018 00:45
URI: https://oak.novartis.com/id/eprint/33706

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