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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2007 |
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| Erschienen: |
2007 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:50 |
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| Enthalten in: |
Journal of medicinal chemistry - 50(2007), 16 vom: 09. Aug., Seite 3928-36 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hanson, Julien [VerfasserIn] |
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| Anmerkungen: |
Date Completed 09.11.2007 Date Revised 20.11.2014 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM171473418 |
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| 100 | 1 | |a Hanson, Julien |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2007 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 09.11.2007 | ||
| 500 | |a Date Revised 20.11.2014 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Guanidines |2 NLM | |
| 650 | 7 | |a Nitriles |2 NLM | |
| 650 | 7 | |a Nitrobenzenes |2 NLM | |
| 650 | 7 | |a Platelet Aggregation Inhibitors |2 NLM | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 650 | 7 | |a Receptors, Thromboxane A2, Prostaglandin H2 |2 NLM | |
| 650 | 7 | |a Sulfonylurea Compounds |2 NLM | |
| 650 | 7 | |a Calcium |2 NLM | |
| 650 | 7 | |a SY7Q814VUP |2 NLM | |
| 700 | 1 | |a Dogné, Jean-Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Ghiotto, Jérémie |e verfasserin |4 aut | |
| 700 | 1 | |a Moray, Anne-Lise |e verfasserin |4 aut | |
| 700 | 1 | |a Kinsella, B Therese |e verfasserin |4 aut | |
| 700 | 1 | |a Pirotte, Bernard |e verfasserin |4 aut | |
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