Chemokine monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to the inflammatory sites by binding to its receptor CCR2, which belongs to G-protein-coupled transmembrane receptor superfamily. RS-102895 is a spiropiperidine compound that acts as an antagonist of MCP-1 to block CCR2 binding with an IC50 value of 360 nM. An inhibition of MCP-1-induced calcium influx by RS-102895 was observed in CCR2-CHL cells with an IC50 value of 32 nM. RS-102895 also inhibited MCP-3-induced calcium influx with IC50 at 130 nM[1]. When decidual stromal cells (DSCs) were treated with 1 ng/mL IL-33 and 100 ng/mL RS-102895 for 48 hours, the proliferation and invasiveness of DSCs were significantly decreased[2]. When mice were dosed with RS-102895 every 6 hours at 5 mg/kg i.p. for a total of 4 treatments, the recruitment of inflammatory monocytes to vaccine draining lymph nodes was significantly reduced at both 12 and 24 hours post immunization. Also in mice immunized with 1 µg HA1, an influenza antigen, and boosted for 10 days, 5 consecutive treatments of 5 mg/kg RS102895 administered 6 hours apart by i.p. injection significantly increased interferon gamma responses and the production of anti-HA1 IgG[3].
作用机制
RS-102895 prevents MCP-1 from binding to CCR2 by occupying the same binding-site, the inter-helical bundle region on the extracellular side of CCR2 receptor[1].
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