A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1
Sironi, M.; Guglielmotti, A.; Polentarutti, N.; Fioretti, F.; Milanese, C.; Romano, M.; Vigini, C.; Coletta, I.; Sozzani, S.; Bernasconi, S.; Vecchi, A.; Pinza, M.; Mantovani, A.
European Cytokine Network 10(3): 437-442
1999
ISSN/ISBN: 1148-5493 PMID: 10477401 Document Number: 499939
Blocking chemokine production or action is a major target for pharmacological intervention in different human diseases. Bindarit (2-methyl-2-((1-(phenylmethyl)-1H-indazol-3yl)methoxy)propanoic acid) dose-dependently inhibited MCP-1 and TNF-alpha production induced in vitro in monocytes by LPS and Candida albicans. It did not affect the production of the cytokines IL-1, IL-6, or the chemokines IL-8, MIP-1alpha and RANTES. In the air pouch model in mice, oral treatment reduced monocyte recruitment and local MCP-1 production, induced by carrageenan or IL-1 injection. In NZB/W mice, a model of lupus nephritis, oral treatment prolonged survival and delayed the onset of proteinuria. The results presented here show that bindarit is a preferential inhibitor of the production of MCP-1 in vitro and in vivo and suggest that its beneficial effects in models of joint and kidney inflammation are related to its anti-MCP-1 action. It is therefore possible to selectively and differentially regulate che mokines by targeting their production with small synthetic molecules.