Structure Property Relationships of Carboxylic Acid Isosteres

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• 作者：Pierrik Lassalas ; Bryant Gay ; Caroline Lasfargeas ; Michael J. James ; Van Tran ; Krishna G. Vijayendran ; Kurt R. Brunden ; Marisa C. Kozlowski ; Craig J. Thomas ; Amos B. Smith III ; Donna M. Huryn ; Carlo Ballatore
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3183-3203
• 全文大小：873K
• 年卷期：0
• ISSN：1520-4804

文摘

The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure–property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.