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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
14
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pubmed:dateCreated |
2010-7-29
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pubmed:abstractText |
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
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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 |
Jul
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AndersonWayne BWB,
pubmed-author:BednarRodney ARA,
pubmed-author:BoguskyMichael JMJ,
pubmed-author:BreslinMichael JMJ,
pubmed-author:BrunoJoseph GJG,
pubmed-author:CabaluTamara DTD,
pubmed-author:ColemanPaul JPJ,
pubmed-author:CoxChristopher DCD,
pubmed-author:CuiDonghuiD,
pubmed-author:DoranScott MSM,
pubmed-author:GarsonSusan LSL,
pubmed-author:HarrellC MeachamCM,
pubmed-author:HartmanGeorge DGD,
pubmed-author:KoblanKen SKS,
pubmed-author:LemaireWeiW,
pubmed-author:McGaugheyGeorgia BGB,
pubmed-author:MercerSwati PSP,
pubmed-author:MurphyKathy LKL,
pubmed-author:PrueksaritanontThomayantT,
pubmed-author:ReissDuane RDR,
pubmed-author:RengerJohn JJJ,
pubmed-author:RoeckerAnthony JAJ,
pubmed-author:RollerShaneS,
pubmed-author:SchreierJohn DJD,
pubmed-author:TangCuyueC,
pubmed-author:WhitmanDavid BDB,
pubmed-author:WinrowChristopher JCJ,
pubmed-author:YoungSteven DSD
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pubmed:issnType |
Electronic
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pubmed:day |
22
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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 |
5320-32
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pubmed:meshHeading |
pubmed-meshheading:20565075-Animals,
pubmed-meshheading:20565075-Azepines,
pubmed-meshheading:20565075-Biological Availability,
pubmed-meshheading:20565075-CHO Cells,
pubmed-meshheading:20565075-Cricetinae,
pubmed-meshheading:20565075-Cricetulus,
pubmed-meshheading:20565075-Dogs,
pubmed-meshheading:20565075-Humans,
pubmed-meshheading:20565075-Male,
pubmed-meshheading:20565075-Microsomes, Liver,
pubmed-meshheading:20565075-Radioligand Assay,
pubmed-meshheading:20565075-Rats,
pubmed-meshheading:20565075-Rats, Sprague-Dawley,
pubmed-meshheading:20565075-Rats, Transgenic,
pubmed-meshheading:20565075-Receptors, G-Protein-Coupled,
pubmed-meshheading:20565075-Receptors, Neuropeptide,
pubmed-meshheading:20565075-Sleep,
pubmed-meshheading:20565075-Sleep Initiation and Maintenance Disorders,
pubmed-meshheading:20565075-Stereoisomerism,
pubmed-meshheading:20565075-Structure-Activity Relationship,
pubmed-meshheading:20565075-Telemetry,
pubmed-meshheading:20565075-Triazoles,
pubmed-meshheading:20565075-Wakefulness
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pubmed:year |
2010
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pubmed:articleTitle |
Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia.
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pubmed:affiliation |
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. chris_cox@merck.com
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pubmed:publicationType |
Journal Article,
In Vitro
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