Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

被引：32

作者：

Koltun, Dmitry O. ^{[1
]}

Vasilevich, Natalya I. ^{[2
]}

Parkhill, Eric Q. ^{[1
]}

Glushkov, Andrei I. ^{[2
]}

Zilbershtein, Timur M. ^{[2
]}

Mayboroda, Elena I. ^{[2
]}

Boze, Melanie A. ^{[1
]}

Cole, Andrew G. ^{[3
]}

Henderson, Ian ^{[3
]}

Zautke, Nathan A. ^{[4
]}

Brunn, Sandra A.

Chu, Nancy ^{[5
]}

Hao, Jia ^{[5
]}

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] NNT Ltd, ASINEX, Moscow 125480, 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 / 11期

关键词：

Stearoyl CoA desaturase (SCD); HEPG2; assay; Microsomal assay; Tissue partition; Tissue distribution; Saturation index; FATTY-ACID; MICE; DISCOVERY; OBESITY; GENE; DISRUPTION; METABOLISM; POTENT;

D O I：

10.1016/j.bmcl.2009.04.004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We discovered a structurally novel SCD (Delta 9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta 5 and Delta 6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3050 / 3053

页数：4

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