Synthesis and pharmacological evaluation of 2-aryloxy/arylamino-5- cyanobenzenesulfonylureas as novel thromboxane A2 receptor antagonists

Sylvie Mireille Bambi-Nyanguile, Julien Hanson, Annie Ooms, Lutfiye Alpan, Philippe Kolh, Jean-Michel Dogne, Bernard Pirotte

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

Résumé

New series of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized and evaluated as thromboxane A2 receptor (TP receptor) antagonists. A functional pharmacological test was used, which consisted of measuring the inhibition of intracellular calcium mobilization in a model of mammalian cell line that specifically over-expressed the individual TPα or TPβ isoforms. 2-Arylamino-5-cyanobenzenesulfonylureas exhibited virtually identical affinity and/or functional activity than 2-aryloxy-5- cyanobenzenesulfonylureas for both TPα and TPβ, but some 2-aryloxy-substituted compounds showed increased selectivity for TPβ relative to TPα. Several compounds were found to be as potent as the 2-arylamino-5-nitrobenzenesulfonylurea reference compound BM-573, supporting the view that the bioisosteric replacement of the nitro group by a cyano group was tolerated. TP receptor antagonist activity of the most promising molecules was confirmed in a platelet aggregation assay using the TP receptor agonist U-46619 as a proaggregant. Three compounds (7e, 7h and 8h) were identified as leads for further non-clinical pharmacological and toxicological studies. © 2013 Elsevier Masson SAS. All rights reserved.

langue originaleAnglais
Pages (de - à)32-40
Nombre de pages9
journalEuropean Journal of Medicinal Chemistry
Volume65
Les DOIs
Etat de la publicationPublié - 23 sept. 2013

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