Design, synthesis, and SAR study of a series of N-alkyl-N'-[2-(aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine as selective antagonists of the TPalpha and TPbeta isoforms of the human thromboxane A2 receptor.
The prostanoid thromboxane (TX)A2 exerts its proaggregant and constrictive actions upon binding to the specific TXA2 receptor (TP), a member of the G-protein coupled receptor superfamily. In humans, TXA2 signals through two distinct TP isoforms, TPalpha and TPbeta. Herein, we describe the design, synthesis, and SAR study of a series of original N-alkyl-N'-[2-(aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine. The SAR study was based on the results of a functional assay, TP-mediated intracellular calcium ([Ca2+]i) mobilization performed on the two separate isoforms. Optimal nature and position of several structural moieties was defined for both activity and selectivity toward TPalpha and TPbeta isoforms. Three compounds (9h, 9af, and 9ag), showing increased selectivity for TPbeta relative to TPalpha (23.2:1, 18.1:1, 19.9:1, respectively), were selected for further experiments, and their activity was confirmed in a platelet aggregation assay. This study represents the first extended SAR study dealing with the identification of isoform selective antagonists for the human TXA2 receptor.
Hanson
Julien
J
Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, 1 Avenue de l'Hôpital, B-4000 Liège, Belgium. J.Hanson@ulg.ac.be
Dogné
Jean-Michel
JM
Ghiotto
Jérémie
J
Moray
Anne-Lise
AL
Kinsella
B Therese
BT
Pirotte
Bernard
B
D000328:Adult; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D006146:Guanidines; D009570:Nitriles; D009578:Nitrobenzenes; D010975:Platelet Aggregation Inhibitors; D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds; D002118:Calcium