Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Rooms 10307, 10309, and 10315, 245 North 15th Street, Philadelphia, PA 19102, USA.
Molecules. 2020 Mar 21;25(6):1430. doi: 10.3390/molecules25061430.
Fostemsavir/temsavir is an investigational HIV-1 entry inhibitor currently in late-stage clinical trials. Although it holds promise to be a first-in-class Env-targeted entry inhibitor for the clinic, issues with bioavailability relegate its use to salvage therapies only. As such, the development of a small molecule HIV-1 entry inhibitor that can be used in standard combination antiretroviral therapy (cART) remains a longstanding goal for the field. We previously demonstrated the ability of extending the chemotypes available to this class of inhibitor as the first step towards this overarching goal. In addition to poor solubility, metabolic stability is a crucial determinant of bioavailability. Therefore, in this short communication, we assess the metabolic stabilities of five of our novel chemotype entry inhibitors. We found that changing the piperazine core region of temsavir alters the stability of the compound in human liver microsome assays. Moreover, we identified an entry inhibitor with more than twice the metabolic stability of temsavir and demonstrated that the orientation of the core replacement is critical for this increase. This work further demonstrates the feasibility of our long-term goal-to design an entry inhibitor with improved drug-like qualities-and warrants expanded studies to achieve this.
福斯特玛韦/替诺福韦酯是一种处于后期临床研究阶段的新型 HIV-1 进入抑制剂。尽管它有望成为临床首创的 Env 靶向进入抑制剂，但由于生物利用度的问题，其只能用于挽救治疗。因此，开发一种可用于标准联合抗逆转录病毒疗法（cART）的小分子 HIV-1 进入抑制剂仍然是该领域的一个长期目标。我们之前已经证明，通过扩展该类抑制剂的化学类型，是实现这一总体目标的第一步。除了溶解度差之外，代谢稳定性也是生物利用度的关键决定因素。因此，在本简短通讯中，我们评估了我们的五种新型化学型进入抑制剂的代谢稳定性。我们发现，改变替诺福韦酯的哌嗪核心区域会改变化合物在人肝微粒体测定中的稳定性。此外，我们鉴定出一种进入抑制剂的代谢稳定性是替诺福韦酯的两倍多，并且表明核心取代的方向对于这种增加至关重要。这项工作进一步证明了我们长期目标的可行性——设计出具有改善的药物样特性的进入抑制剂——并需要进行更多的研究来实现这一目标。
