Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes

Title
Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes
Authors
한서정Suvarna H. PagireHaushabhau S. PagireGwi Bin LeeHyun Jung KwakJi Young KimKi Young KimSang Dal RheeJeong Im RyuJin Sook SongMyung Ae BaeMi-jin ParkDooseop KimDuck Hyung LeeJin Hee Ahn
Issue Date
2015-08
Publisher
European journal of medicinal chemistry
Citation
VOL 101-735
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.
URI
http://pubs.kist.re.kr/handle/201004/67373
ISSN
0223-5234
Appears in Collections:
KIST Publication > Article
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