C(4)-烷基取代的呋喃基环丁烯二酮作为强效的、口服生物可利用的CXCR2和CXCR1受体拮抗剂。
C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists.
作者信息
Chao Jianhua, Taveras Arthur G, Chao Jianping, Aki Cynthia, Dwyer Michael, Yu Younong, Purakkattle Biju, Rindgen Diane, Jakway James, Hipkin William, Fosetta James, Fan Xuedong, Lundell Daniel, Fine Jay, Minnicozzi Michael, Phillips Jonathan, Merritt J Robert
机构信息
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
出版信息
Bioorg Med Chem Lett. 2007 Jul 1;17(13):3778-83. doi: 10.1016/j.bmcl.2007.04.016. Epub 2007 Apr 10.
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.
开发了一系列以环丁烯二酮为中心的C(4)-烷基取代呋喃基类似物作为有效的CXCR2和CXCR1拮抗剂。化合物16对IL-8与受体的结合表现出强效抑制活性（CXCR2的Ki = 1 nM，IC(50)=1.3 nM；CXCR1的Ki = 3 nM，IC(50)=7.3 nM），并且对Gro-α和IL-8诱导的人中性粒细胞迁移均表现出强效抑制作用（趋化作用：CXCR2的IC(50)=0.5 nM，CXCR1的IC(50)=37 nM）。此外，16在大鼠、小鼠、猴子和狗中均显示出良好的口服药代动力学特征。
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