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rdf:type |
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lifeskim:mentions |
umls-concept:C0036751,
umls-concept:C0205314,
umls-concept:C0220781,
umls-concept:C0243076,
umls-concept:C0597357,
umls-concept:C0598594,
umls-concept:C0679622,
umls-concept:C1522538,
umls-concept:C1707689,
umls-concept:C1880355,
umls-concept:C1883254
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pubmed:issue |
15
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pubmed:dateCreated |
2010-8-5
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:ArbanRobertoR,
pubmed-author:BertaniBarbaraB,
pubmed-author:BisonSilviaS,
pubmed-author:BorrielloManuelaM,
pubmed-author:BromidgeSteven MSM,
pubmed-author:CavanniPaoloP,
pubmed-author:Dal FornoGiovannaG,
pubmed-author:Di-FabioRomanoR,
pubmed-author:DonatiDanieleD,
pubmed-author:FontanaStefanoS,
pubmed-author:GianottiMassimoM,
pubmed-author:GordonLaurie JLJ,
pubmed-author:GranciEnricaE,
pubmed-author:LeslieColin PCP,
pubmed-author:MocciaLucaL,
pubmed-author:PasquarelloAlessandraA,
pubmed-author:SartoriIlariaI,
pubmed-author:SavaAnnaA,
pubmed-author:WatsonJeannette MJM,
pubmed-author:WorbyAngelaA,
pubmed-author:ZonziniLauraL,
pubmed-author:ZucchelliValeriaV
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pubmed:issnType |
Electronic
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pubmed:day |
12
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5827-43
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:20590088-Animals,
pubmed-meshheading:20590088-Anti-Anxiety Agents,
pubmed-meshheading:20590088-Antidepressive Agents,
pubmed-meshheading:20590088-Benzoxazines,
pubmed-meshheading:20590088-Callithrix,
pubmed-meshheading:20590088-Cell Line,
pubmed-meshheading:20590088-Cerebral Cortex,
pubmed-meshheading:20590088-Cricetinae,
pubmed-meshheading:20590088-Cricetulus,
pubmed-meshheading:20590088-Cytochrome P-450 Enzyme System,
pubmed-meshheading:20590088-Ether-A-Go-Go Potassium Channels,
pubmed-meshheading:20590088-Guinea Pigs,
pubmed-meshheading:20590088-Humans,
pubmed-meshheading:20590088-Male,
pubmed-meshheading:20590088-Microsomes, Liver,
pubmed-meshheading:20590088-Protein Binding,
pubmed-meshheading:20590088-Radioligand Assay,
pubmed-meshheading:20590088-Rats,
pubmed-meshheading:20590088-Rats, Sprague-Dawley,
pubmed-meshheading:20590088-Serotonin 5-HT1 Receptor Antagonists,
pubmed-meshheading:20590088-Serotonin Plasma Membrane Transport Proteins,
pubmed-meshheading:20590088-Structure-Activity Relationship
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pubmed:year |
2010
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pubmed:articleTitle |
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).
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pubmed:affiliation |
Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. stevebromidge@gmail.com
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pubmed:publicationType |
Journal Article,
In Vitro
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