Kirby Samuel A, Dowd Cynthia S
Department of Chemistry, George Washington University, Washington DC 20052.
Med Chem Res. 2022 Feb;31(2):207-216. doi: 10.1007/s00044-021-02766-x. Epub 2021 Jul 23.
Phosphoryl prodrugs are key compounds in drug development. Biologically active phosphoryl compounds often have negative charges on the phosphoryl group, and as a result, frequently have poor pharmacokinetic (PK) profiles. The use of lipophilic moieties bonded to the phosphorus (or attached oxygen atoms) masks the negative charge of the phosphoryl group, cleavage releasing the active molecule. The use of prodrugs to improve the PK of active parent molecules is an essential step in drug development. This review highlights promising trends in terminal elimination half-life, C, clearance, oral bioavailability, and cLogP in phosphoryl prodrugs. We focus on specific prodrug families: esters, amidates, and ProTides. We conclude that moderating lipophilicity is a key part of prodrug success. This type of evaluation is important for drug development, regardless of clinical application. It is our hope that this analysis, and future ones like it, will play a significant role in prodrug evolution.
磷酰基前药是药物开发中的关键化合物。具有生物活性的磷酰基化合物在磷酰基上通常带有负电荷，因此，其药代动力学（PK）特性往往较差。与磷（或连接的氧原子）相连的亲脂性部分可掩盖磷酰基的负电荷，通过裂解释放出活性分子。利用前药改善活性母体分子的药代动力学是药物开发中的关键步骤。本综述重点介绍了磷酰基前药在终末消除半衰期、血药浓度-时间曲线下面积（AUC）、清除率、口服生物利用度和计算脂水分配系数（cLogP）方面的良好趋势。我们重点关注特定的前药家族：酯类、酰胺类和ProTides。我们得出结论，调节亲脂性是前药成功的关键部分。这种类型的评估对药物开发很重要，无论其临床应用如何。我们希望这种分析以及未来类似的分析将在促进前药的发展中发挥重要作用。
