title: Synthesis and pharmacological evaluation of 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas as novel thromboxane A₂ receptor antagonists.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, Drug Research Center, University of Liege, 1, Avenue de l'Hôpital, Sart-Tilman, B-4000 Liege, Belgium.
authors.forename: Sylvie-Mireille
authors.initials: SM
authors.lastname: Bambi-Nyanguile
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Annie
authors.initials: A
authors.lastname: Ooms
authors.forename: Lutfiye
authors.initials: L
authors.lastname: Alpan
authors.forename: Philippe
authors.initials: P
authors.lastname: Kolh
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C586273:5-cyanobenzenesulfonylurea; D009570:Nitriles; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds
keywords: 2-Aryloxy/arylamino-5-cyanobenzenesulfonylureas; Antiplatelet agents; G-protein coupled receptor; GPCR; IP(3); PLC; TP receptor; TXA(2); TXS; Thromboxane receptor antagonists; inositol 1,4,5-triphosphate; phospholipase C; thromboxane A(2); thromboxane A(2) receptor; thromboxane synthase