Referenced in: none

Automatically associated channels: Kv11.1

Title: Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/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).

Authors: 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 Gordon, Enrica Granci, Colin P Leslie, Luca Moccia, Alessandra Pasquarello, Ilaria Sartori, Anna Sava, Jeannette M Watson, Angela Worby, Laura Zonzini, Valeria Zucchelli

Journal, date & volume: J. Med. Chem., 2010 Aug 12 , 53, 5827-43

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20590088

Abstract
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-HT(1A/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-HT(1A/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.