Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120
Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120
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DOI：
10.1021/acs.jmedchem.7b00179
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发表时间：
2017-04-13
影响因子：
7.3
通讯作者：
Debnath, Asim K.
中科院分区：
文献类型：
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作者：
Curreli, Francesca;Kwon, Young Do;Debnath, Asim K.
在我们试图优化的铅HIV-1进入拮抗剂，NBD-11021，我们在这项研究中提出了合理的设计和合成的60个新的类似物和测定其抗病毒活性在一个单一的循环和多细胞感染试验，以获得一个全面的结构-活性关系（SAR）。这些化合物中的两种，NBD-14088和NBD-14107，在针对大组Env假型病毒的单循环测定中，与先导进入拮抗剂相比，显示出抗病毒活性的显著改善。类似化合物NBD-14010的X射线结构证实了新设计化合物的结合模式。这些化合物的体外ADMET特征与最有效的附着抑制剂BMS-626529相当，BMS-626529的前药目前正在进行III期临床试验。本文提出的系统研究有望为改善这一系列化合物的效价、毒性和ADMET特征铺平道路，并有可能进入早期临床前开发。
In our attempt to optimize the lead HIV-1 entry antagonist, NBD-11021, we present in this study the rational design and synthesis of 60 new analogues and determination of their antiviral activity in a single-cycle and a multicycle infection assay to derive a comprehensive structure-activity relationship (SAR). Two of these compounds, NBD-14088 and NBD-14107, showed significant improvement in antiviral activity compared to the lead entry antagonist in a single-cycle assay against a large panel of Env-pseudotyped viruses. The X-ray structure of a similar compound, NBD-14010, confirmed the binding mode of the newly designed compounds. The in vitro ADMET profiles of these compounds are comparable to that of the most potent attachment inhibitor BMS-626529, a prodrug of which is currently undergoing phase III clinical trials. The systematic study presented here is expected to pave the way for improving the potency, toxicity, and ADMET profile of this series of compounds with the potential to be moved to the early preclinical development.