Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides

被引：26

作者：

Serrano-Wu, Michael H. ^{[1
]}

Coppola, Gary M. ^{[1
]}

Gong, Yongjin ^{[1
]}

Neubert, Alan D. ^{[1
]}

Chatelain, Ricardo ^{[2
]}

Clairmont, Kevin B. ^{[2
]}

Commerford, Renee ^{[2
]}

Cosker, Theresa ^{[3
]}

Daniels, Thomas ^{[2
]}

Hou, Ying ^{[1
]}

Jain, Monish ^{[3
]}

Juedes, Marlene ^{[4
]}

Li, Lisha ^{[2
]}

Mullarkey, Tara ^{[2
]}

Rocheford, Erik ^{[2
]}

Sung, Moo Je ^{[1
]}

Tyler, Andrew ^{[2
]}

Yang, Qing ^{[2
]}

Yoon, Taeyoung ^{[1
]}

Hubbard, Brian K. ^{[2
]}

机构：

[1] Novartis Inst Biomed Res, Dept Global Discovery Chem, Cambridge, MA 02139 USA

[2] Novartis Inst Biomed Res, Dept Cardiovasc & Metab, Cambridge, MA 02139 USA

[3] Novartis Inst Biomed Res, Dept Metab & Pharmacokinet, Cambridge, MA 02139 USA

[4] Novartis Inst Biomed Res, Dept Translat Sci, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 05期

关键词：

DGAT1; triglyceride synthesis; efflux; OBESITY; POTENT; IDENTIFICATION; RESISTANCE; DISCOVERY; GENE;

D O I：

10.1021/ml3000512

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.

引用

页码：411 / 415

页数：5

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