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
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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2006 |
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| Erschienen: |
2006 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
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| Enthalten in: |
Journal of medicinal chemistry - 49(2006), 12 vom: 15. Juni, Seite 3701-9 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hanson, Julien [VerfasserIn] |
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| Themen: |
8W8T17847W |
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| Anmerkungen: |
Date Completed 31.07.2006 Date Revised 10.12.2019 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM163366799 |
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| 100 | 1 | |a Hanson, Julien |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2006 | |
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| 500 | |a Date Completed 31.07.2006 | ||
| 500 | |a Date Revised 10.12.2019 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Guanidines |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 Sulfones |2 NLM | |
| 650 | 7 | |a Urea |2 NLM | |
| 650 | 7 | |a 8W8T17847W |2 NLM | |
| 700 | 1 | |a Reynaud, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Qiao, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Devel, Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Moray, Anne-Lise |e verfasserin |4 aut | |
| 700 | 1 | |a Renard, Jean-François |e verfasserin |4 aut | |
| 700 | 1 | |a Kelley, Leanne P |e verfasserin |4 aut | |
| 700 | 1 | |a Winum, Jean-Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Montero, Jean-Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Kinsella, B Therese |e verfasserin |4 aut | |
| 700 | 1 | |a Pirotte, Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Pace-Asciak, Cecil R |e verfasserin |4 aut | |
| 700 | 1 | |a Dogné, Jean-Michel |e verfasserin |4 aut | |
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