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)

被引：41

作者：

Bromidge, Steven M. ^{[1
]}

Arban, Roberto ^{[2
]}

Bertani, Barbara ^{[2
]}

Bison, Silvia ^{[2
]}

Borriello, Manuela ^{[2
]}

Cavanni, Paolo ^{[2
]}

Dal Forno, Giovanna ^{[2
]}

Di-Fabio, Romano ^{[2
]}

Donati, Daniele ^{[2
]}

Fontana, Stefano ^{[2
]}

Gianotti, Massimo ^{[2
]}

Gordon, Laurie J. ^{[1
]}

Granci, Enrica ^{[2
]}

Leslie, Colin P. ^{[2
]}

Moccia, Luca ^{[2
]}

Pasquarello, Alessandra ^{[2
]}

Sartori, Ilaria ^{[2
]}

Sava, Anna ^{[2
]}

Watson, Jeannette M. ^{[1
]}

Worby, Angela ^{[1
]}

Zonzini, Laura ^{[2
]}

Zucchelli, Valeria ^{[2
]}

机构：

[1] GlaxoSmithKline, Neurosci CEDD, Harlow CM19 5AW, Essex, England

[2] Med Res Ctr, I-37135 Verona, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

关键词：

HERG POTASSIUM CHANNELS; 5-HT; 3,4-DIHYDRO-2H-BENZOXAZINONES; TRANSPORTERS;

D O I：

10.1021/jm100482n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5827 / 5843

页数：17

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