PF-4136309 exhibits potent human chemotaxis activity (IC50=3.9 nM) and effectiveness in a whole blood assay (IC50=19 nM), with IC50 values of 16 nM and 2.8 nM in mouse and rat chemotaxis assays, respectively. It strongly inhibits CCR2-mediated signaling events, such as intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation, with IC50 values of 3.3 nM and 0.5 nM, respectively. In hERG patch clamp assays, PF-4136309 inhibits the hERG potassium current with an IC50 of 20 μM. PF-4136309 does not inhibit cytochrome P450 (CYP), with IC50 values of >30 μM against major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and is not a CYP inducer at concentrations up to 30 μM[1].
体内研究
PF-4136309 (2 mg/kg) shows a moderate half-life of 2.5 hours in rats and 2.4 hours in dogs following intravenous (iv) administration. When given orally at 10 mg/kg, it is absorbed quickly, achieving peak concentrations (Tmax) at 1.2 hours in rats and 0.25 hours in dogs. The half-life is similar between iv and oral (po) dosing in both species. PF-4136309 demonstrates good absorption, with an oral bioavailability of 78% in both species[1].
体外研究
PF-4136309 exhibits potent human chemotaxis activity (IC50=3.9 nM) and effectiveness in a whole blood assay (IC50=19 nM), with IC50 values of 16 nM and 2.8 nM in mouse and rat chemotaxis assays, respectively. It strongly inhibits CCR2-mediated signaling events, such as intracellular calcium mobilization and ERK (extracellular signal-regulated kinase) phosphorylation, with IC50 values of 3.3 nM and 0.5 nM, respectively. In hERG patch clamp assays, PF-4136309 inhibits the hERG potassium current with an IC50 of 20 μM. PF-4136309 does not inhibit cytochrome P450 (CYP), with IC50 values of >30 μM against major CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and is not a CYP inducer at concentrations up to 30 μM[1].
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