title: Synthesis and pharmacological evaluation of novel nitrobenzenic thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor.
abstract: Thromboxane A(2) (TXA(2)) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA(2) receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA(2) are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPalpha and TPbeta, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N'-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N'-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N' '-cyanoguanidines and outline their pharmacological evaluation using the individual TPalpha and TPbeta isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPalpha or TPbeta. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmacy, Natural and Synthetic Drugs Research Centre, University of Liège, 1, Av. de l'Hôpital, B-4000 Liège, Belgium. J.hanson@ulg.ac.be
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Denis
authors.initials: D
authors.lastname: Reynaud
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.forename: Philippe
authors.initials: P
authors.lastname: Devel
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Moray
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Renard
authors.forename: Leanne P
authors.initials: LP
authors.lastname: Kelley
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montero
authors.forename: B Therese
authors.initials: BT
authors.lastname: Kinsella
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Pace-Asciak
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
mesh_terms: D000328:Adult; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D002522:Chlorocebus aethiops; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020033:Protein Isoforms / Q000187:drug effects; D011869:Radioligand Assay; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D006146:Guanidines; D009578:Nitrobenzenes; D010975:Platelet Aggregation Inhibitors; D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013450:Sulfones; D014508:Urea