Design and Synthesis of Novel Tricyclic Benzoxazines as Potent 5-HT1A/B/D Receptor Antagonists Leading to the Discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045)
| Autor: | Ilaria Sartori, Laura Zonzini, Laurie J. Gordon, Angela Worby, Stefano Fontana, Manuela Borriello, Silvia Bison, Jeannette M. Watson, Steven Mark Bromidge, Giovanna Dal Forno, Colin Philip Leslie, Alessandra Pasquarello, Anna Sava, Luca G. Moccia, Barbara Bertani, Roberto Arban, Daniele Donati, Enrica Granci, Valeria Zucchelli, Paolo Cavanni, Massimo Gianotti, Romano Di-Fabio |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 53:5827-5843 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100482n |
| Popis: | Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT1A/B/D receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT1A/B/D receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden. |
| Databáze: | OpenAIRE |
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