AMG 487

AMG 487是一种有效的趋化因子(C-X-C模块)受体3(CXCR3)选择性拮抗剂,对 I-IP-10和I-ITAC的IC50值分别为8 nM和8.2 nM[1].

AMG 487是一种8-azaquinazolinone,可以防止趋化因子 I-IP-10和I-ITAC结合到CXCR3上.在细胞试验中,AMG 487抑制CXCR3介导的细胞迁移,对I-IP-10\I-ITAC和MIG的IC50值分别为8 nM\15 nM和36 nM.AMG 487也被发现可抑制ITAC诱导的钙动员,IC50值为5 nM.在细胞中,AMG 487被CYP3A4和CYP3A5转化为M1(pyridyl N-oxide AMG 487)和M2(O-deethylated AMG 487).据报道,M2代谢物可以竞争性抑制CYP3A,Ki值为0.75 μM[1,2].

参考文献：
[1] Johnson M, Li AR, Liu J, Fu Z, Zhu L, Miao S, Wang X, Xu Q, Huang A, Marcus A, Xu F, Ebsworth K, Sablan E, Danao J, Kumer J, Dairaghi D, Lawrence C, Sullivan T, Tonn G, Schall T, Collins T, Medina J.  Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3339-43.
[2] Tonn GR, Wong SG, Wong SC, Johnson MG, Ma J, Cho R, Floren LC, Kersey K, Berry K, Marcus AP, Wang X, Van Lengerich B, Medina JC, Pearson PG, Wong BK.  An inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)-N-{1-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing. Drug Metab Dispos. 2009 Mar;37(3):502-13.