4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs

被引：6

作者：

Yang, Shyh-Ming ^{[1
]}

Tang, Yuting ^{[1
]}

Rano, Thomas ^{[1
]}

Lu, Huajun ^{[1
]}

Kuo, Gee-Hong ^{[1
]}

Gaul, Michael D. ^{[1
]}

Li, Yaxin ^{[1
]}

Ho, George ^{[1
]}

Lang, Wensheng ^{[1
]}

Conway, James G. ^{[1
]}

Liang, Yin ^{[1
]}

Lenhard, James M. ^{[1
]}

Demarest, Keith T. ^{[1
]}

Murray, William V. ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Cardiovasc & Metab Res, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 05期

关键词：

Stearoyl-CoA desaturase; SCD1; inhibitors; Desaturation index; obesity; LIVER; DISCOVERY; GENE; MICE; CHOLESTEROL; EFFICACY; SERIES; ACIDS;

D O I：

10.1016/j.bmcl.2013.12.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1437 / 1441

页数：5

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