ABSTRACT
A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Cycloheptanes/chemical synthesis , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Hypolipidemic Agents/chemical synthesis , Keto Acids/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Cycloheptanes/pharmacokinetics , Cycloheptanes/pharmacology , Diacylglycerol O-Acyltransferase/genetics , Eating/drug effects , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Keto Acids/pharmacokinetics , Keto Acids/pharmacology , Liver/metabolism , Mice , Mice, Mutant Strains , Stereoisomerism , Structure-Activity Relationship , Triglycerides/metabolism , Urea/pharmacokinetics , Urea/pharmacology , Weight LossABSTRACT
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.