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J Med Chem. 2016 Apr 14;59(7):3183-203. doi: 10.1021/acs.jmedchem.5b01963. Epub 2016 Mar 30.

Structure Property Relationships of Carboxylic Acid Isosteres.

Author information

1
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
2
Center for Neurodegenerative Disease Research, University of Pennsylvania , 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States.
3
National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda, Maryland 20850, United States.

Abstract

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.

PMID:
26967507
PMCID:
PMC4833640
DOI:
10.1021/acs.jmedchem.5b01963
[Indexed for MEDLINE]
Free PMC Article

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