title: Structure Property Relationships of Carboxylic Acid Isosteres.
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.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Pierrik
authors.initials: P
authors.lastname: Lassalas
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Bryant
authors.initials: B
authors.lastname: Gay
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lasfargeas
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania , 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Van
authors.initials: V
authors.lastname: Tran
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Krishna G
authors.initials: KG
authors.lastname: Vijayendran
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania , 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Marisa C
authors.initials: MC
authors.lastname: Kozlowski
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda, Maryland 20850, United States.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.|Center for Neurodegenerative Disease Research, University of Pennsylvania , 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010666:Phenylpropionates / Q000737:chemistry*; D010949:Plasma / Q000737:chemistry* / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D010666:Phenylpropionates