Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
Le Bihan, YV
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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 (1)H-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.
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry)
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Xenobiotica; the fate of foreign compounds in biological systems, 2016, pp. 1 - 23