Development and evaluation of pharmacological agents targeting chemokine receptors.
Chemokine receptors belong to one of the most pharmacologically exploited proteins, the G-protein-coupled receptors. Drugs that target these receptors make up greater than 45% of all known marketed medicines. Several excellent reviews published recently have concentrated on the biology, pathophysiology, and molecular mechanisms of action of the chemokines [C. Gerard, B.J. Rollins, Nat. Immunol. 2 (2001) 108; C.R. Mackay, Nat. Immunol. 2 (2001) 95; M. Thelen, Nat. Immunol. 2 (2001) 129] and the reader is directed toward them to gain a thorough understanding of the importance of this growing family of proteins. Although some background will be given here to aid in an understanding of the medical importance of chemokines, this review will focus on the rapid advances that have been made in identifying and characterizing chemokine receptor antagonists, by discussing their efficacy in animal models of disease as well as detailing their progression through human clinical trials. This approach is exemplified by specific reference to CCR1 and CCR5, which are the most advanced chemokine receptor programs.
Horuk
Richard
R
Department of Immunology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA. Horuk@Pacbell.net
D000818:Animals; D065100:CCR5 Receptor Antagonists; D002986:Clinical Trials as Topic; D015195:Drug Design; D004345:Drug Industry; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D054389:Receptors, CCR1; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; D054389:Receptors, CCR1; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D019204:GTP-Binding Proteins