Small-molecule chemokine receptor

SB225002 was among the first small-molecule chemokine receptor antagonists described, and it has been used in animal models to inhibit IL-8-induced neutrophil margination (White et al, 1998). A modification of this compound, with an IC50 for blockade of CXCL8 binding of 9.3 nM, attenuates leukocyte infiltration into the synovium in models of acute and chronic arthritis in rabbits (Podolin et al, 2002). 

Chemokines are small chemotactic cytokines that act as important messenger molecules between cells of the immune system. Chemokines produce their effects by activating a family of G-protein-coupled receptors. Chemokine receptors are all seven-transmembrane glycoproteins that are structurally related. They may be characterized into those that bind to specific ligands, or those that bind several chemokine ligands. There are also virally encoded (viral) chemokine receptors that represent shared receptors that have been transduced into the viral genome during evolutionary history (Premack and SchaU 1996). 

Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Anti-microb Agents Chemother 2005 49(l 1 ) 4721 —4732. 

Sabroe I, Peck MJ, Van Keulen BJ, et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000 275(34) 25985-25992. 

Widdowson KL, Elliott JD, Veber DF, et al. Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor. J Med Chem 2004 47(6) 1319-1321. 

Smith, S., Zhang, C., LaRosa, G., Jaffee, B., Yang, H., Eddy, P., Lu, C., Uttamsingh, V., Horlick, R., Harriman, G. and Flynn, D. (2006) Design, synthesis, and progress toward optimisation of potent small molecule antagonists of CC chemokine receptor 8 (CCR8). Journal of Medicinal Chemistry, 49, 2669-2672. 

Onuffer, J. J., and Horuk, R. (2002). Chemokines, chemokine receptors and small-molecule antagonists Recent developments. Trends Pharmacol. Sci. 23, 459-467. 

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