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-imi
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- 作者：Steven M. Bromidge ; Roberto Arban ; Barbara Bertani ; Silvia Bison ; Manuela Borriello ; Paolo Cavanni ; Giovanna Dal Forno ; Romano Di-Fabio ; Daniele Donati ; Stefano Fontana ; Massimo Gianotti ; Laurie J. Go
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 12, 2010
- 年：2010
- 卷：53
- 期：15
- 页码：5827-5843
- 全文大小：1233K
- 年卷期：v.53,no.15(August 12, 2010)
- ISSN：1520-4804
文摘
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--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.