Nonacidic Chemotype Possessing N-Acylated Piperidine Moiety as Potent Farnesoid X Receptor (FXR) Antagonists

被引：13

作者：

Teno, Naoki ^{[1
,2
]}

Yamashita, Yukiko ^{[3
]}

Ig, Yusuke ^{[3
]}

Fujimori, Ko ^{[4
]}

Une, Mizuho ^{[1
,3
]}

Nishimaki-Mogami, Tomoko ^{[5
]}

Hiramoto, Takie ^{[1
]}

Gohda, Keigo ^{[6
]}

机构：

[1] Hiroshima Int Univ, Grad Sch Pharmaceut Sci, 5-1-1 Hirokoshingai, Kure, Hiroshima 7370112, Japan

[2] Hiroshima Int Univ, Fac Clin Nutr, 5-1-1 Hirokoshingai, Kure, Hiroshima 7370112, Japan

[3] Hiroshima Int Univ, Fac Pharmaceut Sci, 5-1-1 Hirokoshingai, Kure, Hiroshima 7370112, Japan

[4] Osaka Univ Pharmaceut Sci, Fac Pharmaceut Sci, 4-20-1 Nasahara, Takatsuki, Osaka 5691094, Japan

[5] Natl Inst Hlth Sci, Setagaya Ku, Kamiyoga 1-18-1, Tokyo 1588501, Japan

[6] Kansai CAMM Kansai, Comp Aided Mol Modeling Res Ctr, 3-32-302 Tsuto, Nishinomiya, Hyogo 6638241, Japan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 02期

基金：

日本学术振兴会;

关键词：

FXR antagonists; benzimidazole scaffold; N-acylated piperidine; triglyceride accumulation; ORPHAN NUCLEAR RECEPTOR; BILE-ACID; ADIPOCYTE DIFFERENTIATION; IDENTIFICATION; OPTIMIZATION; DISCOVERY; LIGANDS; HOMEOSTASIS; DERIVATIVES; MODULATORS;

D O I：

10.1021/acsmedchemlett.7b00363

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Famesoid X receptor (FXR) plays a major role in the control of cholesterol metabolism. Antagonizing transcriptional activity of FXR is an effective means to treat the relevant metabolic syndrome. Some of antagonists so far have the charged functions; however, they may negatively affect the pharmacokinetics. We describe herein a structure activity relationship (SAR) exploration of nonacidic FXR antagonist 6 focusing on two regions in the structure and biological evaluation of nonacidic 10 with the characteristic N-acylated piperidine group obtained from SAR studies. As the robust affinity to FXR is feasible with our nonacidic analogue, 10 is among the most promising candidates for in vivo testing.

引用

页码：78 / 83

页数：6

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