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

详细信息    查看全文

• 作者：Michael H. Serrano-Wu ; Gary M. Coppola ; Yongjin Gong ; Alan D. Neubert ; Ricardo Chatelain ; Kevin B. Clairmont ; Renee Commerford ; Theresa Cosker ; Thomas Daniels ; Ying Hou ; Monish Jain ; Marlene Juedes ; Lisha Li ; Tara Mullarkey ; Erik Rocheford ; Moo Je Sung ; Andrew Tyler ; Qing Yang ; Taeyoung Yoon ; Brian K. Hubbard
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：3
• 期：5
• 页码：411-415
• 全文大小：263K
• 年卷期：v.3,no.5(May 10, 2012)
• ISSN：1948-5875

文摘

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.

Keywords:

DGAT1; triglyceride synthesis; efflux