Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

J Med Chem. 2006 Nov 2;49(22):6439-42. doi: 10.1021/jm060955d.

Abstract

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.

MeSH terms

  • Animals
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology*
  • Cyclohexenes / chemistry
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical
  • Female
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Models, Molecular
  • Rats
  • Rats, Zucker
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / pharmacokinetics
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • X-Ray Diffraction

Substances

  • ABT 341
  • Biphenyl Compounds
  • Cyclohexenes
  • Hypoglycemic Agents
  • Serine Proteinase Inhibitors
  • Triazoles
  • cyclohexene
  • Dipeptidyl Peptidase 4