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

作者：Pagire Suvarna H; Pagire Haushabhau S; Lee Gwi Bin; Han Seo Jung; Kwak Hyun Jung; Kim Ji Young; Kim Ki Young; Rhee Sang Dal^*; Ryu Jeong Im; Song Jin Sook; Bae Myung Ae; Park Mi jin; Kim Dooseop; Lee Duck Hyung; Ahn Jin Hee

来源：European Journal of Medicinal Chemistry, 2015, 101: 716-735.

DOI：10.1016/j.ejmech.2015.06.043

• Obesity
• Diabetes
• DGAT1
• Inhibitor
• Adamantane

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.

• 出版日期2015-8-28