A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1.

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]propan oic 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 chemokines by targeting their production with small synthetic molecules.