Discovery of potent, orally bioavailable small-molecule inhibitors of the human CCR2 receptor

ChemMedChem. 2008 Apr;3(4):660-9. doi: 10.1002/cmdc.200700276.


We recently reported the discovery of a series of 2-thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5-diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5-membered heterocyclic substituents at the 4-position gave highly potent CCR2 antagonists. Hydrolysis of the 5-ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Calcium / metabolism
  • Cell Line
  • Chemokine CCL2 / antagonists & inhibitors
  • Drug Stability
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, CCR2 / antagonists & inhibitors*
  • Structure-Activity Relationship


  • CCL2 protein, human
  • CCR2 protein, human
  • Chemokine CCL2
  • Imidazoles
  • Receptors, CCR2
  • Calcium