Abstract
We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.
Keywords:
Adamantane; DGAT1; Diabetes; Inhibitor; Obesity.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adamantane / analogs & derivatives*
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Adamantane / chemistry
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Adamantane / pharmacology
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Animals
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / enzymology
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Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
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Diacylglycerol O-Acyltransferase / metabolism
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Diet, High-Fat / adverse effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Obesity / drug therapy*
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Obesity / enzymology
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Structure-Activity Relationship
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Zebrafish
Substances
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Enzyme Inhibitors
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adamantanecarboxylic acid
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DGAT1 protein, human
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Dgat1 protein, mouse
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Diacylglycerol O-Acyltransferase
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Adamantane