Document Report Card

ID: ALA2062377

Journal: ACS Med Chem Lett

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

Authors: Serrano-Wu MH, Coppola GM, Gong Y, Neubert AD, Chatelain R, Clairmont KB, Commerford R, Cosker T, Daniels T, Hou Y, Jain M, Juedes M, Li L, Mullarkey T, Rocheford E, Sung MJ, Tyler A, Yang Q, Yoon T, Hubbard BK.

Abstract: 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.

CiteXplore: 24900485

DOI: 10.1021/ml3000512