基于具有改善类药性质的α-烷基哌嗪侧链的CXCR4拮抗剂的发现。
Discovery of -Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties.
作者信息
Tahirovic Yesim A, Truax Valarie M, Wilson Robert J, Jecs Edgars, Nguyen Huy H, Miller Eric J, 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, Atlanta, Georgia 30322, United States.
Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States.
出版信息
ACS Med Chem Lett. 2018 Apr 9;9(5):446-451. doi: 10.1021/acsmedchemlett.8b00030. eCollection 2018 May 10.
A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 () in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing -propyl piperazine side chain analogs exemplified by with improved off-target effects as measured in a muscarinic acetylcholine receptor (mAChR) calcium flux assay and in a limited drug safety panel screen. Further efforts to explore SAR and optimize drug properties led to the identification of the '-ethyl--propyl-piperazine tetrahydroisoquinoline derivative and the -propyl-piperazine benzimidazole compound , which gave the best overall profiles with no mAChR or CYP450 inhibition, good permeability in PAMPA assays, and metabolic stability in human liver microsomes.
描述了一系列新型的CXCR4拮抗剂，其具有哌啶基和哌嗪基烷基胺侧链，设计用作丁胺替代物。在SDF-1诱导的钙流测定中，其中几种化合物显示出与母体化合物TIQ-15（）相似的活性。初步的构效关系研究使我们确定了一个含有丙基哌嗪侧链类似物的系列，以在毒蕈碱型乙酰胆碱受体（mAChR）钙流测定和有限的药物安全性面板筛选中测量的具有改善的脱靶效应为例。进一步探索构效关系和优化药物性质的努力导致鉴定出'-乙基 - 丙基 - 哌嗪四氢异喹啉衍生物和丙基 - 哌嗪苯并咪唑化合物，它们给出了最佳的总体概况，没有mAChR或CYP450抑制，在PAMPA测定中具有良好的渗透性，并且在人肝微粒体中具有代谢稳定性。
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