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

Eur J Med Chem. 2015 Aug 28:101:716-35. doi: 10.1016/j.ejmech.2015.06.043. Epub 2015 Jun 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemistry
  • Adamantane / pharmacology
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Diacylglycerol O-Acyltransferase / metabolism
  • Diet, High-Fat / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Structure-Activity Relationship
  • Zebrafish

Substances

  • Enzyme Inhibitors
  • adamantanecarboxylic acid
  • DGAT1 protein, human
  • Dgat1 protein, mouse
  • Diacylglycerol O-Acyltransferase
  • Adamantane