Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors

J Med Chem. 2006 Jun 15;49(12):3520-35. doi: 10.1021/jm051283e.


A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / pharmacology
  • Blood Glucose / analysis
  • Catalytic Domain
  • Crystallography, X-Ray
  • Dipeptidyl Peptidase 4 / metabolism*
  • Drug Stability
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Models, Molecular
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Stereoisomerism
  • Structure-Activity Relationship


  • Anti-Obesity Agents
  • Blood Glucose
  • Hypoglycemic Agents
  • Nitriles
  • Protease Inhibitors
  • Pyrrolidines
  • Dipeptidyl Peptidase 4