cis-2,5-dicyanopyrrolidine inhibitors of dipeptidyl peptidase IV: synthesis and in vitro, in vivo, and X-ray crystallographic characterization

J Med Chem. 2006 Jun 1;49(11):3068-76. doi: 10.1021/jm0600085.

Abstract

Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.

MeSH terms

  • Adenosine Deaminase / chemistry*
  • Adenosine Deaminase Inhibitors*
  • Administration, Oral
  • Animals
  • Biological Availability
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl Peptidase 4 / chemistry*
  • Dogs
  • Glycoproteins / antagonists & inhibitors*
  • Glycoproteins / chemistry*
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Injections, Intravenous
  • Male
  • Mice
  • Models, Molecular
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacology
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • 1-(((1-(hydroxymethyl)cyclopentyl)amino)acetyl)pyrrolidine-2,5-dicarbonitrile
  • Adenosine Deaminase Inhibitors
  • Glycoproteins
  • Hypoglycemic Agents
  • Nitriles
  • Pyrrolidines
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Adenosine Deaminase