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

Donatella Chianelli1, Paul V Rucker1, Jason Roland1

  • 1Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California 92121, United States.

Journal of Medicinal Chemistry
|January 16, 2020
PubMed

Insights

New non-bile acid Farnesoid X receptor (FXR) agonists, like nidufexor, show promise for treating nonalcoholic steatohepatitis (NASH). These compounds target liver fat, inflammation, and fibrosis, advancing to clinical trials.

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Discovery

Background:

  • Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved therapies.
  • Farnesoid X receptor (FXR) agonists demonstrate therapeutic potential by addressing multiple NASH pathologies.
  • Existing FXR agonists include bile acid-derived compounds like obeticholic acid (OCA) and non-bile acid compounds such as tropifexor.

Purpose of the Study:

  • To discover and characterize novel non-bile acid FXR agonists.
  • To identify compounds with efficacy in preclinical models of liver disease.
  • To advance promising drug candidates into clinical development for NASH.

Main Methods:

  • Exploration of a novel tricyclic dihydrochromenopyrazole chemical series.
  • In vitro assessment of FXR agonistic activity.
  • In vivo evaluation of FXR-dependent gene modulation and therapeutic effects.
  • Progression of lead compounds to human clinical trials.

Main Results:

  • Discovery of a novel series of non-bile acid FXR agonists.
  • Identification of nidufexor (LMB763) with partial FXR agonistic activity in vitro.
  • Demonstration of FXR-dependent gene modulation by nidufexor in vivo.
  • Nidufexor advanced to Phase 2 clinical trials for NASH and diabetic nephropathy.

Conclusions:

  • Novel non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core have been identified.
  • Nidufexor represents a promising therapeutic candidate for NASH and potentially other metabolic diseases.
  • The development of non-bile acid FXR agonists offers a new avenue for NASH treatment.

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