CCR2 receptor antagonists: optimization of biaryl sulfonamides to increase activity in whole blood

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7291-4. doi: 10.1016/j.bmcl.2011.10.038. Epub 2011 Oct 19.

Abstract

A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.

MeSH terms

  • Administration, Oral
  • Animals
  • Gene Knock-In Techniques
  • Guanosine 5'-O-(3-Thiotriphosphate) / blood
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding / drug effects
  • Rats
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism
  • Serum Albumin / metabolism
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*

Substances

  • Receptors, CCR2
  • Serum Albumin
  • Sulfonamides
  • Guanosine 5'-O-(3-Thiotriphosphate)