The replacement of the carboxylic acid moiety of a biologically active compound with a surrogate structure is a strategy frequently used in medicinal chemistry to identify new analogs with potentially improved pharmacokinetics and/or pharmacodynamics. Like all isosteric replacements, the success of this strategy is invariably context dependent and no individual bio-isostere can be considered optimal under all circumstances. Carboxylic acid bio-isosteres are typically designed to mimic the carboxylic acid functional group; however, it is the differentiation in structure and properties relative to the parent carboxylic acid compound that is ultimately critical to the success of this strategy. Although numerous carboxylic acid bio-isosteres have been described and successfully deployed in drug design, the identification of alternative surrogates that could complement the existing set with tunable/different properties remains a promising area of research in medicinal chemistry. A schematic of a possible general strategy for the evaluation of novel bio-isosteres is highlighted below. To illustrate this process, candidate bio-isosteres derived from the cyclopentane-1,3-dione scaffold and substituted four-membered ring heterocycles, such as oxetane and thietane, will be discussed.

Design and evaluation of surrogate structures of the carboxylic acid and other acidic functional groups as possible candidates for isosteric replacements

2019 Spring National Meeting

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