Small molecule antagonists of chemokine receptors--is promiscuity a virtue?
A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly "druggable" GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting. In this article, we discuss the successes and failures of chemokine receptor antagonists in the clinic and review a subset of molecules that are documented as having activity at two or more chemokine receptors. It may be that a more permissive approach, targeting several chemokine receptors with a single molecule will provide the next generation of anti-inflammatory drugs.
Pease
James E
JE
Leukocyte Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology & Medicine, South Kensington Campus, London SW7 2AZ, UK. j.pease@imperial.ac.uk
Horuk
Richard
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D008970:Molecular Weight; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013379:Substrate Specificity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019707:Receptors, Chemokine