CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives
CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives
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DOI：
10.1016/j.bmc.2004.10.013
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发表时间：
2005-01-17
影响因子：
3.5
通讯作者：
Sugihara, Y
中科院分区：
文献类型：
--
作者：
Imamura, S;Nishikawa, Y;Sugihara, Y
用1-乙酰基哌啶-4-基取代先前报道的先导结构中的5-氧代吡咯烷-3-基片段导致发现了一系列新的有效的CCR 5拮抗剂。在中心苯环上引入小的疏水取代基增加了结合亲和力，提供了低至亚纳摩尔的CCR 5拮抗剂。所选择的化合物11 f显示出优异的抗CCR 5的抗病毒活性-使用人外周血单核细胞中的HIV-1复制（EC 50 = 0.59 nM）和在狗中可接受的药代动力学特征。(C)2004爱思唯尔有限公司保留所有权利。
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50 = 0.59 nM) and an acceptable pharmacokinetic profile in dogs. (C) 2004 Elsevier Ltd. All rights reserved.