title: Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor.
abstract: The synthesis and the structure of N-isopropyl-N'-[2-(3'-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 microM) with an IC50 value of 0.45 and 0.15 microM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 microM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
authors.affiliation: Department of Pharmacy, University of Namur, Belgium.
authors.forename: J M
authors.initials: JM
authors.lastname: Dogné
authors.forename: J
authors.initials: J
authors.lastname: Wouters
authors.forename: S
authors.initials: S
authors.lastname: Rolin
authors.forename: C
authors.initials: C
authors.lastname: Michaux
authors.forename: L
authors.initials: L
authors.lastname: Pochet
authors.forename: F
authors.initials: F
authors.lastname: Durant
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: B
authors.initials: B
authors.lastname: Masereel
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016718:Arachidonic Acid / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: C121719:BM 500; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D016718:Arachidonic Acid; D013930:Thromboxane-A Synthase