Discovery of XL335 (WAY-362450), a Highly Potent, Selective, and Orally Active Agonist of the Farnesoid X Receptor (FXR)

被引：136

作者：

Flatt, Brenton ^{[1
]}

Martin, Richard ^{[1
]}

Wang, Tie-Lin ^{[1
]}

Mahaney, Paige

Murphy, Brett ^{[1
]}

Gu, Xiao-Hui ^{[1
]}

Foster, Paul ^{[2
]}

Li, Jiali ^{[3
]}

Pircher, Parinaz ^{[3
]}

Petrowski, Mary ^{[3
]}

Schulman, Ira ^{[3
]}

Westin, Stefan ^{[3
]}

Wrobel, Jay ^{[6
]}

Yan, Grace ^{[4
]}

Bischoff, Eric ^{[5
]}

Daige, Chris ^{[5
]}

Mohan, Raju ^{[1
]}

机构：

[1] Exelixis Co, Dept Med Chem, San Diego, CA 92121 USA

[2] Exelixis Co, Dept Biol Struct, San Diego, CA 92121 USA

[3] Exelixis Co, Dept Mol Biol, San Diego, CA 92121 USA

[4] Exelixis Co, Dept Lead Discovery, San Diego, CA 92121 USA

[5] Exelixis Co, Dept Pharmacol, San Diego, CA 92121 USA

[6] Wyeth Ayerst Res, Chem & Screening Sci, Collegeville, PA 19426 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 04期

关键词：

NUCLEAR RECEPTOR; BILE-ACID; IDENTIFICATION; LIGANDS;

D O I：

10.1021/jm8014124

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Azepino[4,5-b]indoles have been identified as potent agonists of the famesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC50 = 4 nM, Eff = 149%). Oral administration of 6m to LDLR-/- mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

引用

页码：904 / 907

页数：4

共 27 条

[1]

*AM CHEM SOC, 2008, 235 NAT M AM CHEM SO

[2] Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor [J].