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

•A series of novel 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized.•The newly synthesized compounds were tested in vitro and ex vivo as thromboxane A2 receptor antagonists.•Some of the tested compounds showed potent thromboxane A2 receptor antagonist activity.•Three compounds (7e, 7h and 8h) were identified as leads for further pharmacological and toxicological studies.

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.

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