Aldehyde oxidase and its contribution to the metabolism of a structurally novel, functionally selective GABAA alpha5-subtype inverse agonist.
(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 was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5-containing receptors, which enhances performance in animal models of cognition. The routes of metabolism of this compound in rat, dog, rhesus monkey and human in vitro systems, and in vivo in rat, dog and rhesus monkey have been characterized. The current study demonstrates that both a cytosolic oxidative reaction and cytochrome P450 play important roles in the metabolism of the compound. Chemical inhibition studies showed the oxidation in human cytosol to be catalysed predominantly by aldehyde oxidase rather than the related enzyme, xanthine oxidase. The aldehyde oxidase-mediated metabolites were present in vitro and in vivo in both rat and rhesus monkey, and also in vitro in man. They were absent both in vitro and in vivo in dog.
O'Connor
D
D
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, UK. desmond_oconnor@merck.com
Jones
P
P
Chambers
M S
MS
Maxey
R
R
Szekeres
H J
HJ
Szeto
N
N
Scott-Stevens
P
P
Macleod
A M
AM
Braun
M
M
Cato
B
B