Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis
Year: 2020
Type: article
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.
Source: Journal of Medicinal Chemistry
Authors: Donatella Chianelli, Paul V. Rucker, Jason Roland, David C. Tully, John Nelson, Xiaodong Liu, Badry Bursulaya, Eloy D. Hernandez, Jane Wu, Mahavir Prashad, Thierry Schlama, Yugang Liu, Alan Chu, James Schmeits, David J. Huang, Robert Hill, Dingjiu Bao, Jocelyn Zoll, Young Kim, Todd Groessl, Peter McNamara, Bo Liu, Wendy Richmond, Ignacio Sancho-Martinez, Andrew Phimister, H. Martin Seidel, Michael K. Badman, Sean B. Joseph, Bryan Laffitte, Valentina Molteni
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
OpenAlex ID: W2999594699