Development of Novel Benzomorpholine Class of Diacylglycerol
Acyltransferase I Inhibitors
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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
(<b>23n</b>). 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 <b>23n</b> 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
