CC Chemokine Receptor-1 (CCR1) Antagonist

BX 471 (1) is a non-peptide CC chemokine receptor-1 (CCR1) antagonist.¹⁾ 1 is able to displace the CCR1 ligands as shown in Table 1. 1 has also greatly higher selectivity for CCR1 than 28 other G-protein-coupled receptors on K_i basis (>10000 fold).¹⁾
He et al. showed that 1 attenuates systemic inflammatory response during sepsis.²⁾ Blocking CCR1 by 1 downregulated ICAM-1, P-selectin, and E-selectin expression at mRNA and protein levels. On the other hand, Lebre et al. reported that 1 blocked CCL5/RANTES-induced migration of rheumatoid arthritis monocytes isolated from the patients.³⁾ Furthermore, Anders et al. showed that 1 blocks macrophage and T-cell recruitment to the renal interstitium of autoimmune mice (MRL^lpr/lpr).⁴⁾

References

• 1) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1
  • M. Liang, C. Mallari, M. Rosser, H. P. Ng, K. May, S. Monahan, J. G. Bauman, I. Islam, A. Ghannam, B. Buckman, K. Shaw, G.-P. Wei, W. Xu, Z. Zhao, E. Ho, J. Shen, H. Oanh, B. Subramanyam, R. Vergona, D. Taub, L. Dunning, S. Harvey, R. M. Snider, J. Hesselgesser, M. M. Morrissey, H. D. Perez, R. Horuk, J. Biol. Chem. 2000, 275, 19000.
• 2) Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis
  • M. He, R. Horuk, S. M. Moochhala, M. Bhatia, Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 292, G1173.
• 3) Why CCR2 and CCR5 Blockade Failed and Why CCR1 Blockade Might Still Be Effective in the Treatment of Rheumatoid Arthritis
  • M. C. Lebre, C. E. Vergunst, I. Y. K. Choi, S. Aarrass, A. S. F. Oliveira, T. Wyant, R. Horuk, K. A. Reedquist, P. P. Tak, PLoS One 2011, 6, e21772.
• 4) Late Onset of Treatment with a Chemokine Receptor CCR1 Antagonist Prevents Progression of Lupus Nephritis in MRL-Fas(lpr) Mice
  • H.-J. Anders, E. Belemezova, V. Eis, S. Segerer, V. Vielhauer, G. Perez de Lema, M. Kretzler, C. D. Cohen, M. Frink, R. Horuk, K. L. Hudkins, C. E. Alpers, F. Mampaso, D. Schlöndorff, J. Am. Soc. Nephrol. 2004, 15, 1504.

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