Optimization of 1,4-diazepan-2-one containing dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes

Bioorg Med Chem Lett. 2007 Apr 1;17(7):1903-7. doi: 10.1016/j.bmcl.2007.01.039. Epub 2007 Jan 24.

Abstract

Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).

MeSH terms

  • Administration, Oral
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / pharmacology
  • Chemistry, Pharmaceutical / methods*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Models, Chemical
  • Molecular Conformation
  • Rats
  • Rats, Sprague-Dawley

Substances

  • 1,4-diazepan-2-one
  • Azepines
  • Dipeptidyl-Peptidase IV Inhibitors
  • Enzyme Inhibitors