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

被引：42

作者：

Ballatore, Carlo ^{[1
,2
]}

Soper, James H. ^{[2
]}

Piscitelli, Francesco ^{[1
]}

James, Michael ^{[2
]}

Huang, Longchuan ^{[1
]}

Atasoylu, Onur ^{[1
]}

Huryn, Donna M. ^{[1
]}

Trojanowski, John Q. ^{[2
]}

Lee, Virginia M. -Y. ^{[2
]}

Brunden, Kurt R. ^{[2
]}

Smith, Amos B., III ^{[1
]}

机构：

[1] Univ Penn, Dept Chem, Sch Arts & Sci, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Pathol & Lab Med, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

基金：

美国国家科学基金会;

关键词：

DRUG DESIGN; TETRAZOLE; ANALOGS;

D O I：

10.1021/jm200980u

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 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.

引用

页码：6969 / 6983

页数：15

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