title: Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group.
abstract: Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States; Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 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 St., Philadelphia, PA 19104-6323, United States.
authors.forename: Longchuan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Katie Herbst
authors.initials: KH
authors.lastname: Robinson
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 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 St., Philadelphia, PA 19104-6323, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D002264:Carboxylic Acids; D003517:Cyclopentanes; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; C000595930:4-chloro-N-(3-((2-hydroxy-3-oxocyclopent-1-en-1-yl)methyl)phenethyl)benzenesulfonamide; D000096926:Benzenesulfonamides
keywords: Carboxylic acid bio-isosteres; Cyclopentane-1,2-dione; Thromboxane A(2) receptor