Chemokine receptor antagonists

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

Chemokine Receptors. Table 1 Chemokine receptor antagonists in clinical trial... 

Ribeiro S, Homk R (2005) Chemokine receptor antagonists from the bench to tire clinic. Weinheim, Wiley-VCH, pp 371-402... 

Rathore A, Chatterjee A, Sivarama P, Yamamoto N, Singhal PK, Dhole TN (2008) Association of RANTES -403 G/A, -28 C/G and Inl.l T/C polymorphism with HlV-1 transmission and progression among North Indians. J Med Virol 80 1133-1141 Ribeiro S, Horuk R (2005) The clinical potential of chemokine receptor antagonists. Pharmacol... 

Chemokine or Chemokine-Receptor Antagonists in Clinical Trials... 

Gao P, Zhou XY, Yashiro-Ohtani Y, et al. The unique target specificity of a nonpeptide chemokine receptor antagonist selective blockade of two Thl chemokine receptors CCR5 and CXCR3. J Leukoc Biol 2003 73(2) 273-280. 

Terricabras E, Benjamim C, Godessart N. Drag discovery and chemokine receptor antagonists eppur si muove Autoimmun Rev 2004 3(7-8) 550-556. 

Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol Ther 2005 107(l) 44-58. 

Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett 1997 57(1—3) 117—120. 

Saeki T, Naya A. CCR1 chemokine receptor antagonist. Curr Pharm Des 2003 9(15) 1201-1208. 

McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002 100(4) 1160-1167. 

The development of maraviroc (21), much like other chemokine receptor antagonists, started with a high-throughput screen employing a competition binding assay and led to the hit compound UK-107,543. Chemical optimization of this compound led to the development candidate UK-427,857 during this optimization phase, a parallel characterization of the compounds was performed... 

The success of chemokine receptor antagonists as therapeutics will depend on a number of factors. It is clear that CCR5 antagonists will probably pave the way as the first approved chemokine drugs to treat disease in man. Here the situation is quite clear. The AIDS virus, HIV, utilizes CCR5 as a coreceptor to... 

Ribeiro S, Horuk R. Chemokine receptor antagonists from the bench to the clinic. In Hannan A, Engelhardt B, eds. Leukocyte Trafficking-Molecular mechanism, therapeutic targets, and methods. Weinheim Wiley-VCH 2005 371 402. 

Tokuyama H, Ueha S, Kurachi M, et al. The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis. Int Immunol 2005 17 1023-1034. 

De Clercq E, Schols D. Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. Antiviral Chem Chemother 2001 12 (suppl 1) 19 31. 

Shamovsky, 1., Connolly, S., David, L., Ivanova, S., Norddn, B., Springthorpe, B. and Urbahns, K. (2008) Overcoming undesirable hERG potency of chemokine receptor antagonists using baseline lipophilicity relationships. Journal of Medicinal Chemistry, 51, 1162—1178. 

Three related tetramic acids have been reported from Chaetomium globosum. Two (44, 45) differ in the stereochemistry of the amino acid component, and the third is the methyl ester of 44 [79]. It is claimed that these compounds are chemokine receptor antagonists and can be used to treat HIV-1 infections. 

E4. Eisner, J., Petering, H., Kimmig, D., Wells, T. N., Proudfoot, A. E., and Kapp, A., The CC chemokine receptor antagonist met-RANTES inhibits eosinophil effector functions. Int. Arch. Allergy Immunol. 118, 462—465 (1999). 

Ponath, P. D. (1998) Chemokine receptor antagonists novel therapeutics for inflammation and AIDS. Exp. Opin. Invest. Drugs 7, 1-18. 

II. Macrophage Inflammatory Protein-la Chemokine Receptor Antagonists... 

Fluorobenzyl bicyclic, (VI), and tricyclic amine derivatives prepared by Dunica (6) were effective as MIP-la chemokine receptor antagonists and used in treating inflammatory and autoimmune diseases. 

Mirzadegan, T., Diehl, F., Ebi, B., Bhakta, S., Polsky, L, McCarley, D., Mulkins, M., Weatherhead, G. S., Lapierre, J. M., Dankwardt, J., Morgans, D., Jr., Wilhelm, R., and Jarnagin, K. (2000). Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists Binding to a common chemokine receptor motif within the helical bundle./. Biol. Chem. 275, 25562-25571. 

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