Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

被引：25

作者：

Lachance, Nicolas ^{[1
]}

Gareau, Yves ^{[1
]}

Guiral, Sebastien ^{[2
]}

Huang, Zheng ^{[2
]}

Isabel, Elise ^{[1
]}

Leclerc, Jean-Philippe ^{[1
]}

Leger, Serge ^{[1
]}

Martins, Evelyn ^{[1
]}

Nadeau, Christian ^{[3
]}

Oballa, Renata M. ^{[1
]}

Ouellet, Stephane G. ^{[3
]}

Powell, David A. ^{[1
]}

Ramtohul, Yeeman K. ^{[1
]}

Tranmer, Geoffrey K. ^{[1
]}

Trinh, Thao ^{[3
]}

Wang, Hao ^{[2
]}

Zhang, Lei ^{[2
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Dept Med Chem, Kirkland, PQ H9H 3L1, Canada

[2] Merck Frosst Ctr Therapeut Res, Dept Biochem & Mol Biol, Kirkland, PQ H9H 3L1, Canada

[3] Merck Frosst Ctr Therapeut Res, Dept Basic Pharmaceut Sci, Kirkland, PQ H9H 3L1, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 02期

关键词：

Stearoyl-CoA desaturase inhibitors; SCD inhibitors; Desaturation index; Liver-targeted; MK-8245; ANALOGS;

D O I：

10.1016/j.bmcl.2011.12.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：980 / 984

页数：5

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