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ACS Med Chem Lett. 2014 Jul 24;5(9):1015-20. doi: 10.1021/ml5002085. eCollection 2014 Sep 11.

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

Author information

1
Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
2
School of Pharmacy and Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
3
Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States ; Department of Chemistry, School of Arts and Sciences, and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.

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.

KEYWORDS:

Cyclopentane-1,3-dione; carboxylic acid bioisostere; thromboxane A2; thromboxane receptor antagonists

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