Synthesis and pharmacological evaluation of novel nitrobenzenic thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor

Julien Hanson, Denis Reynaud, Na Qiao, Philippe Devel, Anne-Lise Moray, Jean-François Renard, Leanne P Kelley, Jean-Yves Winum, Jean-Louis Montero, B Therese Kinsella, Bernard Pirotte, Cecil R Pace-Asciak, Jean-Michel Dogné

Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs

Résumé

Thromboxane A(2) (TXA(2)) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA(2) receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA(2) are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPalpha and TPbeta, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N'-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N'-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N' '-cyanoguanidines and outline their pharmacological evaluation using the individual TPalpha and TPbeta isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPalpha or TPbeta. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.
langue originaleAnglais
Pages (de - à)3701-9
Nombre de pages9
journalJournal of Medicinal Chemistry
Volume49
Numéro de publication12
Les DOIs
Etat de la publicationPublié - 15 juin 2006

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