N-[(1R)-1-[3-(4-乙氧基苯基)-3,4-二氢-4-氧代吡啶并[2,3-D]嘧啶-2-基]乙基]-4-氟-N-(3-吡啶基甲基)-3-(三氟甲基)苯乙酰胺

BI-74330 demonstrates potent inhibition of [ ¹²⁵ I]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 [ ¹²⁵ I]CXCL11 binding to CXCR3-CHO cell membranes. NBI-74330 inhibits calcium mobilization in response to CXCL11 and CXCL10 with an IC ₅₀ value of 7 nM for both ligands used at their EC ₈₀ 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 [ ³⁵ S]GTPγS binding in membranes of cells endogenously expressing CXCR3 (H9 cells, IC ₅₀ value 5.5 nM). BI-74330 inhibits CXCL11-induced chemotaxis in these cells with an IC ₅₀ of 3.9 nM. 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.

NBI-74330 (100 mg/kg) results in the formation of an N-oxide metabolite, also an antagonist of CXCR3, in mice. 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.