作为强效 HIV-1 NNRTIs 的 2,4,5-三取代嘧啶类化合物：合理设计、合成、活性评估及晶体结构研究。
2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies.
机构信息
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, Shandong, PR China.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012, Shandong, PR China.
出版信息
J Med Chem. 2021 Apr 8;64(7):4239-4256. doi: 10.1021/acs.jmedchem.1c00268. Epub 2021 Mar 18.
Abstract
There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead led to the identification of a potent inhibitor . yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of toward the NNRTI-adjacent site as a lead development strategy. Furthermore, demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of as a promising anti-HIV-1 drug candidate.
摘要
目前，临床上急需能够有效应对多种 NNRTI 耐药突变的新型人类免疫缺陷病毒 1 型（HIV-1）抑制剂。本文报道了我们为发现具有新型结构的抗 HIV-1 药物而进行的研究工作，该药物对多种 NNRTI 耐药突变具有更好的抑制效果。通过对先导化合物进行结构修饰，我们发现了一种强效抑制剂 。该化合物对 HIV-1 具有很强的抑制活性，并改善了耐药谱，与已批准的药物依曲韦林相比具有更好的效果。共晶结构揭示了 NNIBP 周围的水分子网络在结合和抵御耐药突变方面的关键作用，同时也提示我们可以进一步将 向 NNRTI 相邻部位延伸，作为一种先导化合物开发策略。此外， 还表现出良好的药代动力学和安全性特征，这表明它有可能成为一种有前途的抗 HIV-1 药物候选物。
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2
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3
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ACS Infect Dis. 2020 Aug 14;6(8):2225-2234. doi: 10.1021/acsinfecdis.0c00327. Epub 2020 Jul 17.
4
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Acta Pharm Sin B. 2020 May;10(5):878-894. doi: 10.1016/j.apsb.2019.08.013. Epub 2019 Sep 14.
5
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