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.
MeSH terms
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology
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Biphenyl Compounds / chemical synthesis
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Biphenyl Compounds / pharmacokinetics
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Biphenyl Compounds / pharmacology
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Cycloheptanes / chemical synthesis*
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Cycloheptanes / pharmacokinetics
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Cycloheptanes / pharmacology
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Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
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Diacylglycerol O-Acyltransferase / genetics
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Eating / drug effects
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Humans
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / pharmacokinetics
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Hypolipidemic Agents / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Keto Acids / chemical synthesis*
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Keto Acids / pharmacokinetics
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Keto Acids / pharmacology
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Liver / metabolism
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Mice
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Mice, Mutant Strains
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Stereoisomerism
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Structure-Activity Relationship
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Triglycerides / metabolism
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacokinetics
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Urea / pharmacology
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Weight Loss
Substances
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Anti-Obesity Agents
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Biphenyl Compounds
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Cycloheptanes
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Hypolipidemic Agents
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Isoenzymes
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Keto Acids
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Triglycerides
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Urea
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DGAT1 protein, human
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Dgat1 protein, mouse
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Diacylglycerol O-Acyltransferase