Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
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 and1H-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.
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Angela
A
Hayes
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
N Yi
NY
Mok
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Manjuan
M
Liu
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Ching
C
Thai
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Alan T
AT
Henley
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Butrus
B
Atrash
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Rachel M
RM
Lanigan
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Jemmy
J
Sejberg
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Yann-Vaï
YV
Le Bihan
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Vassilios
V
Bavetsias
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Julian
J
Blagg
a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
Florence I
FI
Raynaud
D042931:Aldehyde Oxidase / Q000037:antagonists & inhibitors*; D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D066244:Proton Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D042931:Aldehyde Oxidase
Aldehyde oxidase; metabolism; pyrido[3,4-d]pyrimidin-4(3H)-one