Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
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发现哌啶-4-基-氨基嘧啶衍生物作为有效的非核苷 HIV-1 逆转录酶抑制剂
DOI：
10.1016/j.ejmech.2015.04.050
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发表时间：
2015
影响因子：
6.7
通讯作者：
Pannecouque Christophe
中科院分区：
文献类型：
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作者：
Wan Zheng-Yong;Yao Jin;Tao Yuan;Mao Tian-Qi;Wang Xin-Long;Lu Yi-Pei;Wang Hai-Feng;Yin Hong;Wu Yan;Chen Fen-Er;De Clercq Erik;Daelemans Dirk;Pannecouque Christophe
设计了一系列新的哌啶-4-基-氨基嘧啶衍生物，其融合了我们小组先前描述的依曲韦林-VRX-480773杂合体的药效团模板和哌啶连接的氨基嘧啶。与依曲韦林-VRX-480773杂交物相比，大多数化合物显示出显著改善的抗野生型HIV-1活性，EC 50值为个位数纳摩尔浓度。还评价了所选化合物对逆转录酶的活性，其IC 50值低于奈韦拉平。在HIV RNA复制的体外模型中观察到的提高的效力部分验证了这类变构嘧啶衍生物抑制逆转录酶的机制，并代表了艾滋病治疗发展的显著进步。
A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine–VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50values in single-digit nanomolar concentrations compared to etravirine–VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50values than that of nevirapine. The improved potency observed in thisin vitromodel of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.