Development of novel benzomorpholine class of diacylglycerol acyltransferase I inhibitors.

Abstract

Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (23n). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound 23n conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge.

• Authors: Gang Zhou, Nicolas Zorn, Pauline Ting, Robert Aslanian, Mingxiang Lin, John Cook, Jean Lachowicz, Albert Lin, Michelle Smith, Joyce Hwa, Margaret van Heek, Scott Walker
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 5 Issue 5 Pg. 544-9 (May 08 2014) ISSN: 1948-5875 [Print] United States
• PMID: 24900877 (Publication Type: Journal Article)