title: Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction.
abstract: (3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (1) was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors and enhances performance in animal models of cognition. The routes of metabolism of this compound in vivo in rat have been well characterised, the identities of the major metabolites are confirmed by synthesis and their biological profiles were evaluated. An unusual oxidation of the pyrazolo[1,5-d][1,2,4]triazine core to the corresponding pyrazolo[1,5-d][1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Braun
authors.forename: Brian P
authors.initials: BP
authors.lastname: Cato
authors.forename: Mark S
authors.initials: MS
authors.lastname: Chambers
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Hobbs
authors.forename: Robert
authors.initials: R
authors.lastname: Maxey
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Szekeres
authors.forename: Nicola
authors.initials: N
authors.lastname: Szeto
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D058785:GABA-A Receptor Agonists; D006868:Hydrolysis; D007555:Isoxazoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D051379:Mice; D008968:Molecular Conformation; D021122:Protein Subunits / Q000819:agonists*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014227:Triazines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; C494554:MRK 016; D021122:Protein Subunits; D014227:Triazines