杂芳基取代的3,4-二氨基-3-环丁-3-烯-1,2-二酮CXCR2/CXCR1受体拮抗剂的合成及构效关系

Synthesis and structure-activity relationships of heteroaryl substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCR1 receptor antagonists.

作者信息

Yu Younong, Dwyer Michael P, Chao Jianping, Aki Cynthia, Chao Jianhua, Purakkattle Biju, Rindgen Diane, Bond Richard, Mayer-Ezel Rosemary, Jakway James, Qiu Hongchen, Hipkin R William, Fossetta James, Gonsiorek Waldemar, Bian Hong, Fan Xuedong, Terminelli Carol, Fine Jay, Lundell Daniel, Merritt J Robert, He Zhenmin, Lai Gaifa, Wu Minglang, Taveras Arthur

机构信息

Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

出版信息

Bioorg Med Chem Lett. 2008 Feb 15;18(4):1318-22. doi: 10.1016/j.bmcl.2008.01.024. Epub 2008 Jan 11.

DOI:10.1016/j.bmcl.2008.01.024

PMID:18242983

Abstract

Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.

摘要

在CXCR2/CXCR1受体拮抗剂的3,4-二氨基环丁-3-烯-1,2-二酮类化合物中开展了全面的构效关系（SAR）研究，以探究杂环在趋化因子受体结合亲和力、功能活性以及大鼠口服暴露方面的作用。结果表明，杂环的性质以及杂环周围所需的取代模式对这类化合物的整体生物学特性有显著影响。与其他杂环衍生物相比，发现呋喃类化合物，特别是4-卤代加合物，对CXCR2和CXCR1受体均具有更高的结合亲和力、功能活性以及大鼠口服暴露量。