C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists
C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists
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DOI：
10.1016/j.bmcl.2007.04.016
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发表时间：
2007-07-01
影响因子：
2.7
通讯作者：
Merritt, J. Robert
中科院分区：
文献类型：
--
作者：
Chao, Jianhua;Taveras, Arthur G.;Merritt, J. Robert
开发了一系列新的以环丁烯二酮为中心的C（4）-烷基取代的呋喃基类似物作为有效的CXCR 2和CXCR 1拮抗剂。化合物16对IL-8与受体的结合表现出有效的抑制活性（CXCR 2 Ki = 1 nM，IC 50 = 1.3 nM; CXCRI Ki = 3 nM，IC 50 = 7.3 nM），并对Gro-alpha和IL-8诱导的hPMN迁移表现出有效的抑制（趋化性：CXCR 2 IC 50 = 0.5 nM，CXCRI IC 50 = 37 nN 1）。此外，16在大鼠、小鼠、猴和犬中显示出良好的经口药代动力学特征。(c)2007爱思唯尔有限公司版权所有。
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, IC50 = 1.3 nM; CXCRI Ki = 3 nM, IC50= 7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC50=0.5nM,CXCRI IC50= 37 nN1). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog. (c) 2007 Elsevier Ltd. All rights reserved.