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

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. [Display omitted] [Display omitted] •A series of adamantane carboxylic acid derivatives has been identified and synthesized.•Diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities of the compounds were evaluated.•The compound 43c showed good in vitro activity and druggability.•The compound 43c showed good in vivo efficacy (lipid lowering efficacy etc.).•The compound 43c may be a promising lead to develop as an anti-obesity/diabetes drug.