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Potent, long-acting cyclopentane-1,3-Dione Thromboxane (A2)-receptor antagonists

Wang, Xiaozhao, Liu, Li, Huang, Longchuan, Herbst-Robinson, Katie, Cornec, Anne-Sophie, James, Michael J., Sugiyama, Shimpei, Bassetto, Marcella, Brancale, Andrea, Trojanowski, John Q., Lee, Virginia M.-Y., Smith, Amos B., Brunden, Kurt R. and Ballatore, Carlo 2014. Potent, long-acting cyclopentane-1,3-Dione Thromboxane (A2)-receptor antagonists. ACS Medicinal Chemistry Letters 5 (9) , pp. 1015-1020. 10.1021/ml5002085

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Abstract

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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Subjects: Q Science > QD Chemistry
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Cyclopentane-1,3-dione; carboxylic acid bioisostere; thromboxane A2; thromboxane receptor antagonists
Publisher: American Chemical Society
ISSN: 1948-5875
Date of First Compliant Deposit: 30 March 2016
Last Modified: 29 Jun 2019 16:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/69385

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