Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.
复制标题
DOI：
10.1021/acs.jmedchem.5b01827
复制
发表时间：
2016-04-28
影响因子：
7.3
通讯作者：
Xie, Lan
中科院分区：
文献类型：
--
作者：
Liu, Na;Wei, Lei;Huang, Li;Yu, Fei;Zheng, Weifan;Qin, Bingjie;Zhu, Dong-Qin;Morris-Natschke, Susan L.;Jiang, Shibo;Chen, Chin-Ho;Lee, Kuo-Hsiung;Xie, Lan
设计、合成了三个系列（6、13和14）新的二芳基苯胺（DAAN）类似物，并评估了其抗HIV效力，特别是针对具有赋予对新一代非核苷逆转录酶抑制剂药物利匹韦林（1b）耐药性的主要突变的E138 K病毒株。然后评估有前途的新化合物的物理化学和相关的药物性质，包括水溶性，log P值和代谢稳定性，以及预测的亲脂性参数的配体效率，配体亲脂性效率和配体效率依赖性亲脂性指数，这与ADME属性配置文件。化合物6a、14 c和14 d显示出针对1b抗性E138 K突变病毒株的高效力以及抗HIV-1活性和所需药物性质之间的良好平衡。从优化未来NNRTI化合物作为临床试验候选物的角度来看，计算建模结果提供了有关R1组如何对E138 K突变体提供更大疗效的有价值信息。
Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R1 group might provide greater efficacy against the E138K mutant.
登录
查看更多内容
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
影响因子：
2.7
作者：
Tian, Xingtao;Qin, Bingjie;Lu, Hong;Lai, Weihong;Jiang, Shibo;Lee, Kuo-Hsiung;Chen, Chin Ho;Xie, Lan
通讯作者：
Xie, Lan
影响因子：
7.3
作者：
Das, K;Clark, AD;Arnold, E
通讯作者：
Arnold, E
影响因子：
7.3
作者：
Janssen, PAJ;Lewi, PJ;Stoffels, P
通讯作者：
Stoffels, P
影响因子：
5.2
作者：
Lambert-Niclot, S.;Charpentier, C.;Marcelin, A. -G.
通讯作者：
Marcelin, A. -G.