具有刚性侧链的新型四氢异喹啉CXCR4拮抗剂的合成
Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains.
作者信息
Jecs Edgars, Miller Eric J, Wilson Robert J, Nguyen Huy H, Tahirovic Yesim A, Katzman Brook M, Truax Valarie M, Kim Michelle B, Kuo Katie M, Wang Tao, Sum Chi S, Cvijic Mary E, Schroeder Gretchen M, Wilson Lawrence J, Liotta Dennis C
机构信息
Department of Chemistry, Emory University, 1515 Dickey Drive NE, Atlanta, Georgia 30322, United States.
Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
出版信息
ACS Med Chem Lett. 2017 Dec 20;9(2):89-93. doi: 10.1021/acsmedchemlett.7b00406. eCollection 2018 Feb 8.
Abstract
A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener was found to be a potent CXCR4 inhibitor (IC = 33 nM in CXCL12-mediated Ca flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist has potential therapeutic application as a single agent or combinatory anticancer therapy.
摘要
报道了强效TIQ15衍生的CXCR4拮抗剂的构效关系研究。在本研究中，对TIQ15侧链进行了限制以改善其药物性质。发现环己基氨基类似物是一种强效的CXCR4抑制剂（在CXCL12介导的钙流中IC = 33 nM），在肝微粒体中稳定性增强，对CYP450（2D6）的抑制作用降低。改进后的CXCR4拮抗剂作为单一药物或联合抗癌疗法具有潜在的治疗应用价值。
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