Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the MCP-1 receptor, CCR2. CCR2 is also a member of the G-protein-coupled seven-transmembrane receptor superfamily. RS 504393 has been identified as a selective CCR2 chemokine receptor antagonist. RS 504393 exhibits IC50 values of 89 nM and >100 μM for inhibition of human recombinant CCR2 and CCR1 receptors respectively.
In vitro, in A549 cell line, RS504393 treatment significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor- stimulation. Additionally, treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1, plasminogen activator inhibitor and CCR2.
Furthermore, in vivo, RS504393 (0.3-3 μg) with CCL2 progressively blocked thermal hyperalgesia dose-dependently in mice. Besides, RS 504393 (5 mg/kg, i.v.) supressed the elevated numbers of leukocytes and increased total protein content in BALF induced by The LPS. Likewise, RS504393 significantly down regulated the LPS-induced elevation of IL-1β, PAI-1 mRNA and protein expressions. RS504393 also significantly suppressed induced lung edema, protein-rich fluid, polymorphonuclear accumulation and bronchial wall thickening induced by LPS. In addition, RS-504393 significantly reduced renal pathology, especially the extensive interstitial fibrosis mediated by decrease in type I collagen synthesis in a UUO model.
In summary, RS504393 has potential to treat inflammatory diseases, such as fibrosis and allergy. Further work still need to be carried out.
Mirzadegan T, et al. 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. J Biol Chem. 2000 Aug 18;275(33):25562-71.