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).
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.
authors.affiliation: Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. stevebromidge@gmail.com
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bromidge
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertani
authors.forename: Silvia
authors.initials: S
authors.lastname: Bison
authors.forename: Manuela
authors.initials: M
authors.lastname: Borriello
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavanni
authors.forename: Giovanna
authors.initials: G
authors.lastname: Dal Forno
authors.forename: Romano
authors.initials: R
authors.lastname: Di-Fabio
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Massimo
authors.initials: M
authors.lastname: Gianotti
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Gordon
authors.forename: Enrica
authors.initials: E
authors.lastname: Granci
authors.forename: Colin P
authors.initials: CP
authors.lastname: Leslie
authors.forename: Luca
authors.initials: L
authors.lastname: Moccia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasquarello
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sartori
authors.forename: Anna
authors.initials: A
authors.lastname: Sava
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
authors.forename: Valeria
authors.initials: V
authors.lastname: Zucchelli
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002144:Callithrix; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C551960:6-(2-(4-(2-methyl-5-quinolinyl)-1-piperazinyl)ethyl)-4H-imidazo(5,1-c)(1,4)benzoxazine-3-carboxamide; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D048588:Benzoxazines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System