Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
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Date
2017-09-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Animals
Humans
Mice
Pyrimidines
Aldehyde Oxidase
Structure-Activity Relationship
Models, Molecular
Proton Magnetic Resonance Spectroscopy
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)
Language
eng
Date accepted
2016-08-25
License start date
2017-09
Citation
Xenobiotica; the fate of foreign compounds in biological systems, 2017, 47 (9), pp. 771 - 777
Publisher
TAYLOR & FRANCIS LTD