Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

被引：55

作者：

Koltun, Dmitry O. ^{[1
]}

Parkhill, Eric Q. ^{[1
]}

Vasilevich, Natalya I. ^{[2
]}

Glushkov, Andrei I. ^{[2
]}

Zilbershtein, Timur M. ^{[2
]}

Ivanov, Alexei V. ^{[2
]}

Cole, Andrew G. ^{[3
]}

Henderson, Ian ^{[3
]}

Zautke, Nathan A. ^{[4
]}

Brunn, Sandra A. ^{[4
]}

Mollova, Nevena ^{[5
]}

Leung, Kwan ^{[5
]}

Chisholm, Jeffrey W. ^{[4
]}

Zablocki, Jeff ^{[1
]}

机构：

[1] CV Therapeut Inc, Dept Med Chem, Palo Alto, CA 94304 USA

[2] ASINEX Ltd, Moscow 123367, Russia

[3] Ligand Pharmaceut Inc, Dept Chem, Cranbury, NJ 08512 USA

[4] CV Therapeut Inc, Dept Pharmacol Sci, Palo Alto, CA 94304 USA

[5] CV Therapeut Inc, Dept Preclin Dev, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 07期

关键词：

Stearoyl CoA; Desaturase; SCD; HEPG2; assay; Microsomal assay; Pteridinone; FATTY-ACIDS; MICE; GENE; DISRUPTION; DISCOVERY; OBESITY;

D O I：

10.1016/j.bmcl.2009.02.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We identified a series of structurally novel SCD (Delta 9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modi. cation of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta 5 and Delta 6 desaturases. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2048 / 2052

页数：5

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