2. Academic Validation
  3. Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

  • J Med Chem. 2020 Apr 23;63(8):3868-3880. doi: 10.1021/acs.jmedchem.9b01621.
Donatella Chianelli 1,  Paul V Rucker 1,  Jason Roland 1,  David C Tully 1 2,  John Nelson 1,  Xiaodong Liu 1,  Badry Bursulaya 1,  Eloy D Hernandez 1,  Jane Wu 1,  Mahavir Prashad 3,  Thierry Schlama 4,  Yugang Liu 3,  Alan Chu 1,  James Schmeits 1,  David J Huang 1,  Robert Hill 1,  Dingjiu Bao 1,  Jocelyn Zoll 1,  Young Kim 1,  Todd Groessl 1,  Peter McNamara 1,  Bo Liu 1,  Wendy Richmond 1,  Ignacio Sancho-Martinez 1,  Andrew Phimister 2,  H Martin Seidel 1,  Michael K Badman 5,  Sean B Joseph 1,  Bryan Laffitte 1,  Valentina Molteni 1
Affiliations

Affiliations

  • 1 Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.
  • 2 Novartis Institutes for Biomedical Research, Emeryville, California 94608, United States.
  • 3 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States.
  • 4 Novartis Pharma AG, Basel 4002, Switzerland.
  • 5 Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, United States.
PMID: 31940200 DOI: 10.1021/acs.jmedchem.9b01621
Abstract

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR Agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR Agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

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