SCH 546738

SCH 546738 is a potent, orally active and non-competitive CXCR3 antagonist, the affinity constant (K_i) of SCH 546738 binding to human CXCR3 receptor is determined to be 0.4 nM in multiple experiments. IC50 & Target: Ki: 0.4 nM (CXCR3 receptor)^[1] In Vitro: The affinity of SCH 546738 binding to human CXCR3 receptor is determined by competition binding analysis using ³⁵S radiolabeled SCH 535390 (a sulfonamide analog of the CXCR3 compound series with a K_d of 0.6 nM) as a competitive tracer. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC₅₀ ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC₉₀ about 10 nM. Competition of human CXCL10 and CXCL11 binding to human CXCR3 by SCH 546738 is determined at various concentrations of [¹²⁵I]hCXCL10 and [¹²⁵I]hCXCL11 around the K_d (50-100 pM) for the receptor. The IC₅₀ of SCH 546738 is constant (~1 or 2 nM) and independent of the input concentrations of either [¹²⁵I]hCXCL10 (25-500 pM) or [¹²⁵I]hCXCL11 (12.5-250 pM), respectively^[1]. In Vivo: SCH 546738 has strong cross-species activities with IC₅₀ of 1.3 nM, 6.4 nM, 5.9 nM and 4.2 nM in inhibiting the binding of [¹²⁵I]hCXCL10 to CXCR3 of monkey, dog, mouse and rat origin, respectively. SCH 546738 is a selective and potent CXCR3 antagonist with a good PK for in vivo studies. In addition, SCH 546738 has a favourable pharmacokinetic profile in rodents, the plasma concentrations of SCH 546738 in Lewis rat and C57BL/6 mouse over 24 hr post-dose. The AUC (0-24 hr) is 7.7 μM.hr in Lewis rat 10 mg/kg (mpk) and is 12.6 μM.hr in C57BL/6 mouse 30 mpk^[1].