Discovery of potent and selective orally bioavailable beta-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors

Bioorg Med Chem Lett. 2005 Jun 15;15(12):3048-52. doi: 10.1016/j.bmcl.2005.04.028.

Abstract

anti-Substituted biaryl beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the beta-methyl substituent with beta-polar substituents, culminating in the discovery of a beta-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / metabolism
  • DNA-Binding Proteins / metabolism
  • Dipeptidyl Peptidase 4 / chemistry*
  • Dipeptidyl Peptidase 4 / metabolism
  • Glucose Tolerance Test
  • Humans
  • Mice
  • Molecular Structure
  • Phenylalanine / chemical synthesis*
  • Phenylalanine / pharmacokinetics
  • Phenylalanine / pharmacology*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity
  • Trans-Activators / metabolism
  • Transcriptional Regulator ERG

Substances

  • Blood Glucose
  • DNA-Binding Proteins
  • ERG protein, human
  • Protease Inhibitors
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Phenylalanine
  • Dipeptidyl Peptidase 4