Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.
Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.
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DOI：
10.1021/jm900136j
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发表时间：
2009-05-28
影响因子：
7.3
通讯作者：
Lee KH
中科院分区：
文献类型：
--
作者：
Qian K;Yu D;Chen CH;Huang L;Morris-Natschke SL;Nitz TJ;Salzwedel K;Reddick M;Allaway GP;Lee KH
在对有效抗hiv药物的持续研究中，设计、合成了17种28,30-二取代白桦酸（BA, 1）衍生物和7种新的3,28-二取代白桦酸类似物，并对其体外抗病毒活性进行了评估。其中，化合物21与HIV进入抑制剂3b （IC9564）和4 （A43-D）相比，具有更好的溶解度和相同的抗HIV效力（EC50: 0.09 μM）。使用环仲胺形成C-28酰胺键，可显著提高衍生物在混合人肝微粒体中的代谢稳定性。其中化合物47和48的EC50值分别为0.007 μM和0.006 μM，具有较强的抗hiv活性。这些结果略好于目前处于IIb期临床试验的bevirimat(2)。化合物47和48应该成为开发下一代代谢稳定的3,28-二取代双功能HIV-1抑制剂的有吸引力的有前途的先导物，作为临床试验候选药物。
In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives, as well as seven novel 3,28-disubstituted BA analogs were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50: 0.09 μM), when compared to HIV entry inhibitors 3b (IC9564) and 4 (A43-D). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 μM and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2), which is currently in Phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
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影响因子：
4.9
作者：
Lai, Weihong;Huang, Li;Chen, Chin-Ho
通讯作者：
Chen, Chin-Ho
影响因子：
2.1
作者：
LEEDS, JP;KIRST, HA
通讯作者：
KIRST, HA
影响因子：
7.3
作者：
Soler, F;Poujade, C;Dereu, N
通讯作者：
Dereu, N
影响因子：
158.5
作者：
Hammer, SM;Katzenstein, DA;Salgo, M
通讯作者：
Salgo, M
影响因子：
3.5
作者：
Huang, L;Ho, P;Chen, CH
通讯作者：
Chen, CH