Potent, Long-Acting Cyclopentane-1,3-Dione Thromboxane (A2)-Receptor Antagonists
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- 作者：Xiaozhao Wang ; Li Liu ; Longchuan Huang ; Katie Herbst-Robinson ; Anne-Sophie Cornec ; Michael J. James ; Shimpei Sugiyama ; Marcella Bassetto ; Andrea Brancale ; John Q. Trojanowski ; Virginia M.-Y. Lee ; Amos B. Smith ; III ; Kurt R. Brunden ; Carlo Ballatore
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：September 11, 2014
- 年：2014
- 卷：5
- 期：9
- 页码：1015-1020
- 全文大小：362K
- ISSN：1948-5875
文摘
A series of derivatives of the known thromboxane A2 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.