Flatt Brenton, Martin Richard, Wang Tie-Lin, Mahaney Paige, Murphy Brett, Gu Xiao-Hui, Foster Paul, Li Jiali, Pircher Parinaz, Petrowski Mary, Schulman Ira, Westin Stefan, Wrobel Jay, Yan Grace, Bischoff Eric, Daige Chris, Mohan Raju
Department of Medicinal Chemistry, Exelixis Inc., 4757 Nexus Centre Drive, San Diego, California 92121, USA.
J Med Chem. 2009 Feb 26;52(4):904-7. doi: 10.1021/jm8014124.
Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid 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 (EC(50) = 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.
氮杂环庚并[4,5-b]吲哚已被确定为法尼醇X受体（FXR）的强效激动剂。通过体外和体内优化，发现6m（XL335，WAY-362450）是一种强效、选择性且口服生物可利用的FXR激动剂（半数有效浓度（EC(50)）=4 nM，效能（Eff）=149%）。给低密度脂蛋白受体敲除（LDLR(-/-)）小鼠口服6m可降低胆固醇和甘油三酯水平。在动脉粥样硬化模型中进行长期给药可显著减少主动脉弓病变。
