(2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

J Med Chem. 2006 Jun 15;49(12):3614-27. doi: 10.1021/jm060015t.

Abstract

A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Calcium Channels, L-Type / drug effects
  • Cell Line
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Muscle Proteins / antagonists & inhibitors
  • Muscle, Skeletal / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis
  • Phenylalanine / chemistry
  • Phenylalanine / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Rabbits
  • Sodium Channels
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • 3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-(1,2,4)triazolo(1,5-a)pyridin-6-ylphenyl)butanamide
  • Calcium Channels, L-Type
  • Hypoglycemic Agents
  • Muscle Proteins
  • NAV1.5 Voltage-Gated Sodium Channel
  • Protease Inhibitors
  • SCN5A protein, human
  • Scn5a protein, mouse
  • Sodium Channels
  • Triazoles
  • Phenylalanine
  • Dipeptidyl Peptidase 4