Potent, Long-Acting Cyclopentane-1,3-Dione Thromboxane (A2)-Receptor Antagonists

被引：5

作者：

Wang, Xiaozhao ^{[1
]}

Liu, Li ^{[2
]}

Huang, Longchuan ^{[1
]}

Herbst-Robinson, Katie ^{[2
]}

Cornec, Anne-Sophie ^{[1
]}

James, Michael J. ^{[2
]}

Sugiyama, Shimpei ^{[1
]}

Bassetto, Marcella ^{[2
]}

Brancale, Andrea ^{[2
]}

Trojanowski, John Q. ^{[2
]}

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

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

Brunden, Kurt R. ^{[2
]}

Ballatore, Carlo ^{[1
,2
]}

机构：

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

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

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 09期

关键词：

Cyclopentane-1,3-dione; carboxylic acid bioisostere; thromboxane A2; thromboxane receptor antagonists; RECEPTOR ANTAGONISTS; TETRAHYDRONAPHTHALENE DERIVATIVES; TERUTROBAN; DISEASE; PERFORM; BIOLOGY; BINDING; EVENTS; DESIGN; STROKE;

D O I：

10.1021/ml5002085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of derivatives of the known thromboxane A(2) prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.

引用

页码：1015 / 1020

页数：6

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