Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.

Abstract

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 25 Pg. 19000-8 (Jun 23 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10748002 (Publication Type: Journal Article)

Chemical References

• CCR1 protein, human
• Ccr1 protein, rat
• DNA, Complementary
• Phenylurea Compounds
• Piperidines
• Receptors, CCR1
• Receptors, Chemokine
• BX 471

Topics

• Administration, Oral
• Animals
• Binding, Competitive
• Cell Line
• DNA, Complementary
• Dogs
• Humans
• Male
• Phenylurea Compounds (administration & dosage, pharmacokinetics, pharmacology)
• Piperidines (administration & dosage, pharmacokinetics, pharmacology)
• Rats
• Rats, Inbred Lew
• Receptors, CCR1
• Receptors, Chemokine (antagonists & inhibitors, genetics, metabolism)