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.
(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.
Jones
Philip
P
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.
Atack
John R
JR
Braun
Matthew P
MP
Cato
Brian P
BP
Chambers
Mark S
MS
O'Connor
Desmond
D
Cook
Susan M
SM
Hobbs
Sarah C
SC
Maxey
Robert
R
Szekeres
Helen J
HJ
Szeto
Nicola
N
Wafford
Keith A
KA
MacLeod
Angus M
AM
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*
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; C494554:MRK 016; D021122:Protein Subunits; D014227:Triazines