Cyclopentane-1,3-dione: A Novel Isostere for the Carboxylic Acid Functional Group. Application to the Design of Potent Thromboxane (A2) Receptor Antagonists

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• 作者：Carlo Ballatore ; James H. Soper ; Francesco Piscitelli ; Michael James ; Longchuan Huang ; Onur Atasoylu ; Donna M. Huryn ; John Q. Trojanowski ; Virginia M.-Y. Lee ; Kurt R. Brunden ; Amos B. Smith ; III
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6969-6983
• 全文大小：1287K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

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鈥揷hemical 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 A₂ 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鈥?b>45) were identified that exhibit nanomolar IC₅₀ 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.