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 pharmacologic al intervention in different human diseases. Bindarit (2-methyl-2-[[1-(phen ylmethyl)-1H-indazol-3yl] methoxyl]propanoic acid) dose-dependently inhibit ed 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, I L-6, or the chemokines IL-8, MIP-1 alpha and RANTES, In the air pouch model in mice, oral treatment reduced monocyte recruitment and local MCP-1 produ ction, 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 preferenti al inhibitor of the production of MCP-1 in vitro and in vivo and suggest th at its beneficial effects in models of joint and kidney inflammation are re lated to its anti-MCP-l action. It is therefore possible to selectively and differentially regulate chemokines by targeting their production with smal l synthetic molecules.