Metabolic Efficacy of Phosphate Prodrugs and the Remdesivir Paradigm.,ACS Pharmacology & Translational Science

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Metabolic Efficacy of Phosphate Prodrugs and the Remdesivir Paradigm.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-07-24 , DOI: 10.1021/acsptsci.0c00076
Andrew J Wiemer _{1,

2}

Affiliation

Drugs that contain phosphates (and phosphonates or phosphinates) have intrinsic absorption issues and are therefore often delivered in prodrug forms to promote their uptake. Effective prodrug forms distribute their payload to the site of the intended target and release it efficiently with minimal byproduct toxicity. The ability to balance unwanted payload release during transit with desired release at the site of action is critical to prodrug efficacy. Despite decades of research on prodrug forms, choosing the ideal prodrug form remains a challenge which is often solved empirically. The recent emergency use authorization of the antiviral remdesivir for COVID-19 exemplifies a new approach for delivery of phosphate prodrugs by parenteral dosing, which minimizes payload release during transit and maximizes tissue payload distribution. This review focuses on the role of metabolic activation in efficacy during oral and parenteral dosing of phosphate, phosphonate, and phosphinate prodrugs. Through examining prior structure–activity studies on prodrug forms and the choices that led to development of remdesivir and other clinical drugs and drug candidates, a better understanding of their ability to distribute to the planned site of action, such as the liver, plasma, PBMCs, or peripheral tissues, can be gained. The structure–activity relationships described here will facilitate the rational design of future prodrugs.

中文翻译：

磷酸盐前药的代谢功效和瑞德西韦范式。

含有磷酸盐（和膦酸盐或次膦酸盐）的药物具有固有的吸收问题，因此通常以前药形式递送以促进其吸收。有效的前药形式将它们的有效载荷分配到预期目标的部位，并以最小的副产物毒性有效地释放它。平衡运输过程中不需要的有效载荷释放与作用部位的期望释放的能力对于前药功效至关重要。尽管对前药形式进行了数十年的研究，但选择理想的前药形式仍然是一个挑战，通常凭经验解决。最近针对 COVID-19 的抗病毒药物瑞德西韦的紧急使用授权举例说明了一种通过肠胃外给药递送磷酸盐前药的新方法，该方法可最大限度地减少运输过程中的有效载荷释放并最大限度地增加组织有效载荷的分布。本综述重点关注代谢激活在磷酸盐、膦酸盐和次膦酸盐前药口服和肠胃外给药期间的功效中的作用。通过检查先前对前药形式的构效研究以及导致瑞德西韦和其他临床药物和候选药物开发的选择，更好地了解它们分布到计划的作用部位（如肝脏、血浆、PBMC）的能力，或外周组织，可以获得。这里描述的构效关系将有助于未来前药的合理设计。通过检查先前对前药形式的构效研究以及导致瑞德西韦和其他临床药物和候选药物开发的选择，更好地了解它们分布到计划的作用部位（如肝脏、血浆、PBMC）的能力，或外周组织，可以获得。这里描述的构效关系将有助于未来前药的合理设计。通过检查先前对前药形式的构效研究以及导致瑞德西韦和其他临床药物和候选药物开发的选择，更好地了解它们分布到计划的作用部位（如肝脏、血浆、PBMC）的能力，或外周组织，可以获得。这里描述的构效关系将有助于未来前药的合理设计。

更新日期：2020-08-14

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