NBI-74330

NBI-74330 is a potent antagonist for CXCR3, and exhibits potent inhibition of (¹²⁵I)CXCL10 and (¹²⁵I)CXCL11 specific binding with K_i of 1.5 and 3.2 nM, respectively. IC50 & Target: Ki: 1.5 nM (CXCL10), 3.2 nM (CXCL11) In Vitro: BI-74330 demonstrates potent inhibition of [¹²⁵I]CXCL11 specific binding to membranes prepared from transfected CHO cells expressing CXCR3 (CXCR3-CHO) (K_i=3.6 nM). NBI-74330 is 12- and 3.5-fold more potent than CXCL9 (K_i=45.2 nM) and CXCL10 (K_i=12.5 nM), respectively, at inhibiting [¹²⁵I]CXCL11 binding to CXCR3-CHO cell membranes. NBI-74330 inhibits calcium mobilization in response to CXCL11 and CXCL10 with an IC₅₀ value of 7 nM for both ligands used at their EC₈₀ concentrations (1 nM for CXCL11 and 30 nM for CXCL10). NBI-74330 specifically inhibits CXCR3-mediated calcium mobilization. NBI-74330 also dose-dependently inhibits CXCL11-induced [³⁵S]GTPγS binding in membranes of cells endogenously expressing CXCR3 (H9 cells, IC₅₀ value 5.5 nM). BI-74330 inhibits CXCL11-induced chemotaxis in these cells with an IC₅₀ of 3.9 nM^[1]. NBI-74330 (30-300 nm, 1-10 μM) produces concentration-dependent, parallel rightward shifts of the CXCL11 E/[A] curve with no significant change in the E/[A] curve maximal response^[2]. In Vivo: NBI-74330 (100 mg/kg) results in the formation of an N-oxide metabolite, also an antagonist of CXCR3, in mice^[2]. Mice treated with 100 mg/kg NBI-74330 (in 1% Na Doc in 0.5% 400Cp Methylcellulose) result in serum concentrations of approximately 1 μM. This concentration is sufficient to fully block the CXCR3 receptor in vivo^[3].