(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

J Med Chem. 2005 Jan 13;48(1):141-51. doi: 10.1021/jm0493156.

Abstract

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Biochemistry / methods
  • Blood Glucose / analysis
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / drug effects*
  • Dipeptidyl Peptidase 4 / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Glucagon / blood
  • Glucagon / drug effects
  • Glucagon-Like Peptide 1
  • Glucose Tolerance Test
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Peptide Fragments / blood
  • Peptide Fragments / drug effects
  • Protein Conformation
  • Protein Precursors / blood
  • Protein Precursors / drug effects
  • Pyrazines / chemistry*
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Rats
  • Sitagliptin Phosphate
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*

Substances

  • Blood Glucose
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Peptide Fragments
  • Protein Precursors
  • Pyrazines
  • Triazoles
  • Glucagon-Like Peptide 1
  • Glucagon
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate