Discovery of carmegliptin: a potent and long-acting dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1109-13. doi: 10.1016/j.bmcl.2009.12.024. Epub 2009 Dec 6.

Abstract

Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Clinical Trials, Phase II as Topic
  • Crystallography, X-Ray
  • Delayed-Action Preparations
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / metabolism
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors* / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors* / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
  • Dogs
  • Drug Design*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / therapeutic use
  • Macaca fascicularis
  • Mice
  • Quinolizines / administration & dosage
  • Quinolizines / chemical synthesis*
  • Quinolizines / therapeutic use
  • Rats
  • Rats, Wistar
  • Rats, Zucker

Substances

  • Delayed-Action Preparations
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Quinolizines
  • carmegliptin
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4

Associated data

  • PDB/3KWF