2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors

J Med Chem. 2005 Jun 30;48(13):4312-31. doi: 10.1021/jm049082i.


The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chemokines, CXC / antagonists & inhibitors*
  • Chemotaxis, Leukocyte / drug effects*
  • Female
  • Humans
  • Ketoprofen / pharmacology
  • Ligands
  • Lymphoma
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / physiology
  • Mice
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Propionates / chemical synthesis
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Receptors, Interleukin-8A / genetics
  • Receptors, Interleukin-8A / metabolism*
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship


  • Chemokines, CXC
  • Ligands
  • Propionates
  • Receptors, Interleukin-8A
  • Recombinant Proteins
  • Ketoprofen