Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV

J Med Chem. 2011 Jan 27;54(2):510-24. doi: 10.1021/jm101016w. Epub 2010 Dec 27.

Abstract

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Biological Availability
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme Inhibitors
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dogs
  • Macaca fascicularis
  • Models, Molecular
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyrimidinones