E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: Structural development study and separation from farnesoid X receptor-agonistic activity

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• 作者：Takashi Misawa^a ; Hisamitsu Hayashi^b ; Makoto Makishima^c ; Yuichi Sugiyama^b ; ; Yuichi Hashimoto^a ; ^{hashimot@iam.u-tokyo.ac.jp}
• 关键词：Bile salt export pump ; Bile acid ; Farnesoid X receptor ; Mutant
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June, 2012
• 卷：22
• 期：12
• 页码：3962-3966
• 文件大小：561 K

摘要

Bile salt export pump (BSEP) is a member of the ATP-binding cassette transmembrane transporter family and mediates biliary excretion of bile acids from hepatocytes. Several BSEP mutants, including Glu297Gly (E297G) and Asp482Gly (D482G), cause progressive familial intrahepatic cholestasis type 2. We previously found that compounds based on GW4064, a representative farnesoid X receptor (FXR) agonist, enhanced E297G BSEP transport activity. Here, we conducted a structure-activity relationship analysis of GW4064 derivatives aimed at separating E297G BSEP-function-promoting activity and FXR-agonistic activity. Among newly synthesized reversed-amide derivatives of previously reported GW4064 analogs 2a-2f, we identified 7c as a selective BSEP function enhancer.