2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2010 Aug 12;53(15):5827-43. doi: 10.1021/jm100482n.
Steven M Bromidge 1,  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
Affiliations

Affiliation

  • 1 Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. [email protected]
PMID: 20590088 DOI: 10.1021/jm100482n
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.

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