Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
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Authors
Hayes, A
Mok, NY
Liu, M
Thai, C
Henley, AT
Atrash, B
Lanigan, RM
Sejberg, J
Le Bihan, Y-V
Bavetsias, V
Blagg, J
Raynaud, FI
Mok, NY
Liu, M
Thai, C
Henley, AT
Atrash, B
Lanigan, RM
Sejberg, J
Le Bihan, Y-V
Bavetsias, V
Blagg, J
Raynaud, FI
Document Type
Journal Article
Date
2017-09-01
Date Accepted
2016-08-25
Abstract
1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and 1H-NMR and showed that C2-substituted derivatives are no longer AO substrates. 4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.
Citation
Xenobiotica; the fate of foreign compounds in biological systems, 2017, 47 (9), pp. 771 - 777
Source Title
Publisher
TAYLOR & FRANCIS LTD
ISSN
0049-8254
eISSN
1366-5928
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)