Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Carlo Ballatore; Bryant Gay; Longchuan Huang; Katie Herbst Robinson; Michael J James; John Q Trojanowski; Virginia M-Y Lee; Kurt R Brunden; Amos B Smith 3rd

doi:10.1016/j.bmcl.2014.07.047

Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4171-5. doi: 10.1016/j.bmcl.2014.07.047. Epub 2014 Jul 23.

Authors

Carlo Ballatore¹, Bryant Gay², Longchuan Huang², Katie Herbst Robinson³, Michael J James³, John Q Trojanowski³, Virginia M-Y Lee³, Kurt R Brunden³, Amos B Smith 3rd²

Affiliations

¹ 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.
² Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States.
³ Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.

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.

Keywords: Carboxylic acid bio-isosteres; Cyclopentane-1,2-dione; Thromboxane A(2) receptor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Crystallography, X-Ray
Cyclopentanes / chemical synthesis
Cyclopentanes / chemistry
Cyclopentanes / pharmacology*
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Receptors, Thromboxane A2, Prostaglandin H2 / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

4-chloro-N-(3-((2-hydroxy-3-oxocyclopent-1-en-1-yl)methyl)phenethyl)benzenesulfonamide
Carboxylic Acids
Cyclopentanes
Receptors, Thromboxane A2, Prostaglandin H2
Sulfonamides

Abstract

Publication types

MeSH terms

Substances

Grants and funding