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

被引：9

作者：

Misawa, Takashi ^{[1
]}

Hayashi, Hisamitsu ^{[2
]}

Makishima, Makoto ^{[3
]}

Sugiyama, Yuichi ^{[2
]}

Hashimoto, Yuichi ^{[1
]}

机构：

[1] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan

[2] Univ Tokyo, Lab Mol Pharmacokinet, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[3] Nihon Univ, Sch Med, Itabashi Ku, Tokyo 1738610, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 12期

基金：

日本学术振兴会;

关键词：

Bile salt export pump; Bile acid; Farnesoid X receptor; Mutant; FAMILIAL INTRAHEPATIC CHOLESTASIS; ORPHAN NUCLEAR RECEPTOR; IDENTIFICATION; FXR; TRANSPORT; ACIDS;

D O I：

10.1016/j.bmcl.2012.04.099

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3962 / 3966

页数：5

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