Vertex Pharmaceuticals Incorporated , 50 Northern Avenue Boston, Massachusetts 02210, United States.
J Med Chem. 2014 Dec 11;57(23):9701-17. doi: 10.1021/jm501000a. Epub 2014 Sep 18.
The acid/base properties of a molecule are among the most fundamental for drug action. However, they are often overlooked in a prospective design manner unless it has been established that a certain ionization state (e.g., quaternary base or presence of a carboxylic acid) appears to be required for activity. In medicinal chemistry optimization programs it is relatively common to attenuate basicity to circumvent undesired effects such as lack of biological selectivity or safety risks such as hERG or phospholipidosis. However, teams may not prospectively explore a range of carefully chosen compound pKa values as part of an overall chemistry strategy or design hypothesis. This review summarizes the potential advantages and disadvantages of both acidic and basic drugs and provides some new analyses based on recently available public data.
分子的酸碱性质是药物作用最基本的性质之一。然而，除非已经确定某种离子化状态（例如，季铵碱或羧酸的存在）似乎是活性所必需的，否则在前瞻性设计中往往会忽略它们。在药物化学优化程序中，通常会降低碱性以避免出现缺乏生物选择性或安全性风险（如 hERG 或磷脂沉积）等不良影响。然而，团队可能不会前瞻性地探索一系列精心选择的化合物 pKa 值，作为整体化学策略或设计假设的一部分。本文综述了酸性药物和碱性药物的潜在优缺点，并基于最近可用的公共数据提供了一些新的分析。
