Abstract：
Carboxylic acids are key pharmacophoric elements in many molecules. They can be seen as a problem by some, due to perceived permeability challenges, potential for high plasma protein binding and the risk of forming reactive metabolites due to acyl-glucuronidation. By others they are viewed more favorably as they can decrease lipophilicity by adding an ionizable center which can be beneficial for solubility, and can add enthalpic interactions with the target protein. However, there are many instances where the replacement of a carboxylic acid with a bioisosteric group is required. This has led to the development of a number of ionizable groups which sufficiently mimic the carboxylic acid functionality whilst improving, for example, the metabolic profile of the molecule in question. An alternative strategy involves replacement of the carboxylate by neutral functional groups. This review initially details carefully selected examples whereby tetrazoles, acyl sulfonamides or isoxazolols have been beneficially utilized as carboxylic acid bioisosteres altering physicohemical properties, interactions with the target and metabolism and/or pharmacokinetics, before delving further into the binding mode of carboxylic acid derivatives with their target proteins. This analysis highlights new ways to consider the replacement of carboxylic acids by neutral bioisosteric groups which either rely on hydrogen bonds or cation-π interactions. It should serve as a useful guide for scientists working in drug discovery.
摘要：
羧酸是许多分子中的关键药效元素。它们可以被一些人视为一个问题，由于感知到的渗透性挑战，高血浆蛋白结合的可能性以及由于酰基-葡糖醛酸化而形成反应性代谢物的风险。其他人认为它们更有利，因为它们可以通过添加可电离中心来降低亲脂性，并能增加与靶蛋白的焓相互作用。然而,在许多情况下,需要用生物等排基团取代羧酸。这导致了许多可电离基团的发展，这些基团充分模拟了羧酸官能团，同时改善了羧酸官能团。例如,所讨论的分子的代谢谱。另一种策略涉及用中性官能团取代羧酸盐。这篇评论最初详细介绍了精心选择的四唑，酰基磺酰胺或异恶唑醇已被有益地用作羧酸生物等排物，改变物理化学特性，与目标和代谢和/或药代动力学的相互作用，在进一步深入研究羧酸衍生物与其靶蛋白的结合模式之前。该分析突出了考虑用中性生物等排基团取代羧酸的新方法，这些基团依赖于氢键或阳离子-π相互作用。它应该成为从事药物发现工作的科学家的有用指南。
