Pyrido[3, 4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution. (2nd September 2017)

• Record Type: Journal Article
• Authors: Hayes, Angela; Mok, N. Yi; Liu, Manjuan; Thai, Ching; Henley, Alan T.; Atrash, Butrus; Lanigan, Rachel M.; Sejberg, Jimmy; Le Bihan, Yann-Vaï; Bavetsias, Vassilios; Blagg, Julian; Raynaud, Florence I.
• Is Part Of: Xenobiotica. Volume 47:Number 9(2017)
• Page Start: 771
• Page End: 777
• Publication Date: 2017-09-02
• Subjects: Aldehyde oxidase -- metabolism -- pyrido[3, 4-d]pyrimidin-4(3H)-one; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2016.1230245
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: 1. We have previously described C8-substituted pyrido[3, 4- d ]pyrimidin-4(3 H )-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(3 H )-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.