杂环多环氨基甲酰基吡啶酮作为 HIV-1 整合酶链转移抑制剂的分子设计和评估。

IF 2.5 4区 医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-07-24 DOI:10.1016/j.bmcl.2024.129902
Toshiyuki Akiyama , Brian A. Johns , Yoshiyuki Taoda , Hiroshi Yoshida , Teruhiko Taishi , Takashi Kawasuji , Hitoshi Murai , Tomokazu Yoshinaga , Akihiko Sato , Takahiro Seki , Mikiko Koyama , Shigeru Miki , Shinobu Kawauchi-Miki , Akemi Kagitani-Suyama , Tamio Fujiwara
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引用次数: 0

摘要

整合酶链转移抑制剂(INSTIs)是抗逆转录病毒疗法中处方量最大的主药。如今,HIV-1 感染的长效治疗需求越来越大。改善药物的药代动力学和抗 HIV-1 活性是开发适合长效制剂的更强效抑制剂的关键,但第二代 INSTIs 具有手性中心,因此很难进行进一步的探索。在这项研究中,我们设计了杂三环和杂双环氨基甲酰基吡啶酮支架,这些支架没有多鲁曲韦 (DTG) 中存在问题的半氨基立体中心。这种支架跳转使得引入多个取代基变得非常容易,利用这些支架进行的结构-活性研究产生了几种性能良好的新药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors

Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure–activity studies using these scaffolds resulted in several leads with promising properties.

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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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