title: Cyclopentane-1,3-dione: a novel isostere for the carboxylic acid functional group. Application to the design of potent thromboxane (A2) receptor antagonists.
abstract: Cyclopentane-1,3-diones are known to exhibit pK(a) values typically in the range of carboxylic acids. To explore the potential of the cyclopentane-1,3-dione unit as a carboxylic acid isostere, the physical-chemical properties of representative congeners were examined and compared with similar derivatives bearing carboxylic acid or tetrazole residues. These studies suggest that cyclopentane-1,3-diones may effectively substitute for the carboxylic acid functional group. To demonstrate the use of the cyclopentane-1,3-dione isostere in drug design, derivatives of a known thromboxane A(2) prostanoid (TP) receptor antagonist, 3-(3-(2-(4-chlorophenylsulfonamido)ethyl)phenyl)propanoic acid (12), were synthesized and evaluated in both functional and radioligand-binding assays. A series of mono- and disubstituted cyclopentane-1,3-dione derivatives (41-45) were identified that exhibit nanomolar IC(50) and K(d) values similar to 12. Collectively, these studies demonstrate that the cyclopentane-1,3-dione moiety comprises a novel isostere of the carboxylic acid functional group. Given the combination of the relatively strong acidity, tunable lipophilicity, and versatility of the structure, the cyclopentane-1,3-dione moiety may constitute a valuable addition to the palette of carboxylic acid isosteres.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States. bcarlo@sas.upenn.edu
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: James H
authors.initials: JH
authors.lastname: Soper
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Longchuan
authors.initials: L
authors.lastname: Huang
authors.forename: Onur
authors.initials: O
authors.lastname: Atasoylu
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011789:Quantum Theory; D011869:Radioligand Assay; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D003517:Cyclopentanes; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013777:Tetrazoles