(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Bioorg Med Chem Lett. 2007 Jan 1;17(1):49-52. doi: 10.1016/j.bmcl.2006.09.099. Epub 2006 Oct 5.

Abstract

Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.

MeSH terms

  • Animals
  • Azepines / chemistry*
  • Azepines / therapeutic use
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / therapeutic use
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / therapeutic use
  • Protein Conformation
  • Pyrazines / chemistry
  • Pyrazines / therapeutic use
  • Rats
  • Rats, Inbred Strains
  • Sitagliptin Phosphate
  • Triazoles / chemistry
  • Triazoles / therapeutic use

Substances

  • 4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one
  • Azepines
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Protease Inhibitors
  • Pyrazines
  • Triazoles
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate