Chianelli, Donatella, Rucker, Paul, Tully, David, Nelson, John, Liu, Xiaodong, Bursulaya, Badry, Hernandez, Eloy , Chu, Alan, Schmeits, James, Hill, Robert, Bao, Dingjiu, Zoll, Jocelyn, Kim, Young, Groessl, Todd, McNamara, Peter, Richmond, Wendy, Sancho Martinez, Ignacio, Badman, Michael, Molteni, Valentina, Jason, Roland, Jane, Wu, David, Huang, Bo, Liu, Andrew, Phimister, Martin, Seidel, Sean, Joseph, Bryan, Laffitte, Prashad, Mahavir, Schlama, Thierry and Liu, Yugang (2020) Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis. Journal of medicinal chemistry, 63 (8). pp. 3868-3880. ISSN 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 have described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we describe 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.

Item Type:	Article
Keywords:	FXR, farnesoid X Receptor; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; BSEP, bile salt export pump; SHP, short heterodimer partner; FGF15/FGF19, fibroblast growth factor 15/19; LMB763, LJN452; NAS
Date Deposited:	21 Oct 2020 00:45
Last Modified:	21 Oct 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41781