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 |
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Authors: | Jones Philip Atack John R Braun Matthew P Cato Brian P Chambers Mark S O'Connor Desmond Cook Susan M Hobbs Sarah C Maxey Robert Szekeres Helen J Szeto Nicola Wafford Keith A MacLeod Angus M |
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Institution: | Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. |
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Abstract: | (3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo1,5-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 pyrazolo1,5-d]1,2,4]triazine core to the corresponding pyrazolo1,5-d]1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed. |
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