"目录号: HY-15320
GPCR/G ProteinImmunology/Inflammation-
NBI-74330 是一种有效的CXCR3拮抗剂，能够抑制 (125I)CXCL10 和 (125I)CXCL11 的特异性结合，Ki值分别为 1.5 和 3.2 nM。
CXCR
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生物活性
Description
NBI-74330 is a potent antagonist forCXCR3, and exhibits potent inhibition of (125I)CXCL10 and (125I)CXCL11 specific binding withKiof 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) (Ki=3.6 nM). NBI-74330 is 12- and 3.5-fold more potent than CXCL9 (Ki=45.2 nM) and CXCL10 (Ki=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 IC50value of 7 nM for both ligands used at their EC80concentrations (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, IC50value 5.5 nM). BI-74330 inhibits CXCL11-induced chemotaxis in these cells with an IC50of 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].
References
[1].Heise CE, et al. Pharmacological characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist. J Pharmacol Exp Ther. 2005 Jun;313(3):1263-71.
[2].Jopling LA, et al. Analysis of the pharmacokinetic/pharmacodynamic relationship of a small molecule CXCR3 antagonist, NBI-74330, using a murine CXCR3 internalization assay. Br J Pharmacol. 2007 Dec;152(8):1260-71.
[3].van Wanrooij EJ, et al. CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):251-7.