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

被引：91

作者：

Chianelli, Donatella ^{[1
]}

Rucker, Paul, V ^{[1
]}

Roland, Jason ^{[1
]}

Tully, David C. ^{[1
,2
]}

Nelson, John ^{[1
]}

Liu, Xiaodong ^{[1
]}

Bursulaya, Badry ^{[1
]}

Hernandez, Eloy D. ^{[1
]}

Wu, Jane ^{[1
]}

Prashad, Mahavir ^{[3
]}

Schlama, Thierry ^{[4
]}

Liu, Yugang ^{[3
]}

Chu, Alan ^{[1
]}

Schmeits, James ^{[1
]}

Huang, David J. ^{[1
]}

Hill, Robert ^{[1
]}

Bao, Dingjiu ^{[1
]}

Zoll, Jocelyn ^{[1
]}

Kim, Young ^{[1
]}

Groessl, Todd ^{[1
]}

McNamara, Peter ^{[1
]}

Liu, Bo ^{[1
]}

Richmond, Wendy ^{[1
]}

Sancho-Martinez, Ignatio ^{[1
]}

Phimister, Andrew ^{[2
]}

Seidel, H. Martin ^{[1
]}

Badman, Michael K. ^{[5
]}

Joseph, Sean B. ^{[1
]}

Laffitte, Bryan ^{[1
]}

Molteni, Valentina ^{[1
]}

机构：

[1] Novartis Res Fdn GNF, Genom Inst, San Diego, CA 92121 USA

[2] Novartis Inst Biomed Res, Emeryville, CA 94608 USA

[3] Novartis Pharmaceut, E Hanover, NJ 07936 USA

[4] Novartis Pharma AG, CH-4002 Basel, Switzerland

[5] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 08期

关键词：

FARNESOID-X-RECEPTOR; HEPATIC STELLATE CELLS; BILE-ACID; NUCLEAR RECEPTOR; OBETICHOLIC ACID; LIPOPROTEIN METABOLISM; LIVER-TRANSPLANTATION; REGULATORY CASCADE; MURINE MODEL; INFLAMMATION;

D O I：

10.1021/acs.jmedchem.9b01621

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3868 / 3880

页数：13

共 44 条

[1] The TGR5 receptor mediates bile acid-induced itch and analgesia [J].

Alemi, Farzad ;

Kwon, Edwin ;

Poole, Daniel P. ;

Lieu, TinaMarie ;

Lyo, Victoria ;

Cattaruzza, Fiore ;

Cevikbas, Ferda ;

Steinhoff, Martin ;

Nassini, Romina ;

Materazzi, Serena ;

Guerrero-Alba, Raquel ;

Valdez-Morales, Eduardo ;

Cottrell, Graeme S. ;

Schoonjans, Kristina ;

Geppetti, Pierangelo ;

Vanner, Stephen J. ;

Bunnett, Nigel W. ;

Corvera, Carlos U. .

JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (04) :1513-1530

[2] Substituted pyrazoles as novel selective ligands for the human dopamine D4 receptor [J].

Bourrain, S ;

Collins, I ;

Neduvelil, JG ;

Rowley, M ;

Leeson, PD ;

Patel, S ;

Emms, F ;

Marwood, R ;

Chapman, KL ;

Fletcher, AE ;

Showell, GA .

BIOORGANIC & MEDICINAL CHEMISTRY, 1998, 6 (10) :1731-1743

[3] Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection [J].

Bowlus, Christopher L. .

HEPATIC MEDICINE-EVIDENCE AND RESEARCH, 2016, 8 :89-95

[4] Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR [J].

Calkin, Anna C. ;

Tontonoz, Peter .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2012, 13 (04) :213-224

[5] The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases [J].

Chalasani, Naga ;

Younossi, Zobair ;

Lavine, Joel E. ;

Charlton, Michael ;

Cusi, Kenneth ;

Rinella, Mary ;

Harrison, Stephen A. ;

Brunt, Elizabeth M. ;

Sanyal, Arun J. .

HEPATOLOGY, 2018, 67 (01) :328-357

[6] Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States [J].

Charlton, Michael R. ;

Burns, Justin M. ;

Pedersen, Rachel A. ;

Watt, Kymberly D. ;

Heimbach, Julie K. ;

Dierkhising, Ross A. .

GASTROENTEROLOGY, 2011, 141 (04) :1249-1253

[7] Bile acids: regulation of synthesis [J].

Chiang, John Y. L. .

JOURNAL OF LIPID RESEARCH, 2009, 50 (10) :1955-1966

[8] Liver Transplantation for Nonalcoholic Steatohepatitis in the US: Temporal Trends and Outcomes [J].

Cholankeril, George ;

Wong, Robert J. ;

Hu, Menghan ;

Perumpail, Ryan B. ;

Yoo, Eric R. ;

Puri, Puneet ;

Younossi, Zobair M. ;

Harrison, Stephen A. ;

Ahmed, Aijaz .

DIGESTIVE DISEASES AND SCIENCES, 2017, 62 (10) :2915-2922

[9] A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis [J].

Fiorucci, S ;

Rizzo, G ;

Antonelli, E ;

Renga, B ;

Mencarelli, A ;

Riccardi, L ;

Orlandi, S ;

Pruzanski, M ;

Morelli, A ;

Pellicciari, R .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 314 (02) :584-595

[10] The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis [J].

Fiorucci, S ;

Antonelli, E ;

Rizzo, G ;

Renga, B ;

Mencarelli, A ;

Riccardi, L ;

Orlandi, S ;

Pellicciari, R ;

Morelli, A .

GASTROENTEROLOGY, 2004, 127 (05) :1497-1512

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