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.
Sironi
M
M
Istituto Ricerche Farmacologiche Mario Negri, via Eritrea, 62, Milan, Italy.
Guglielmotti
A
A
Polentarutti
N
N
Fioretti
F
F
Milanese
C
C
Romano
M
M
Vigini
C
C
Coletta
I
I
Sozzani
S
S
Bernasconi
S
S
Vecchi
A
A
Pinza
M
M
Mantovani
A
A
D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*
D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D007191:Indazoles; D011422:Propionates; C079489:bindarit