Structure Property Relationships of Carboxylic Acid Isosteres

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.