2. Academic Validation
  3. Development of novel benzomorpholine class of diacylglycerol acyltransferase I inhibitors

Development of novel benzomorpholine class of diacylglycerol acyltransferase I inhibitors

  • ACS Med Chem Lett. 2014 Mar 1;5(5):544-9. doi: 10.1021/ml400527n.
Gang Zhou 1,  Nicolas Zorn 1,  Pauline Ting 1,  Robert Aslanian 1,  Mingxiang Lin 1,  John Cook 1,  Jean Lachowicz 1,  Albert Lin 1,  Michelle Smith 1,  Joyce Hwa 1,  Margaret van Heek 1,  Scott Walker 1
Affiliations

Affiliation

  • 1 Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
PMID: 24900877 DOI: 10.1021/ml400527n
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.

Keywords

DGAT1; benzomorpholine; diacylglycerol acyltransferase inhibitor; postprandial triglyceridemia (PPTG).

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