title: 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.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Zorn
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Pauline
authors.initials: P
authors.lastname: Ting
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Lin
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: John
authors.initials: J
authors.lastname: Cook
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Lachowicz
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Albert
authors.initials: A
authors.lastname: Lin
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Smith
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Walker
keywords: DGAT1; benzomorpholine; diacylglycerol acyltransferase inhibitor; postprandial triglyceridemia (PPTG)