Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution

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.

Keywords:

• Aldehyde oxidase
• metabolism
• pyrido[3,4-d]pyrimidin-4(3H)-one

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Avon Foundation for Women [10.13039/100000142], Gift Agreement grant No. 02-2013-52 and Cancer Research UK [10.13039/501100000289], Cancer Research UK [CRUK] grant number C309/A11566.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Supplementary material available online.