dc.contributor.author | Hayes, A | |
dc.contributor.author | Mok, NY | |
dc.contributor.author | Liu, M | |
dc.contributor.author | Thai, C | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Atrash, B | |
dc.contributor.author | Lanigan, RM | |
dc.contributor.author | Sejberg, J | |
dc.contributor.author | Le Bihan, Y-V | |
dc.contributor.author | Bavetsias, V | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Raynaud, FI | |
dc.date.accessioned | 2017-09-19T08:52:12Z | |
dc.date.issued | 2017-09-01 | |
dc.identifier.citation | Xenobiotica; the fate of foreign compounds in biological systems, 2017, 47 (9), pp. 771 - 777 | |
dc.identifier.issn | 0049-8254 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/831 | |
dc.identifier.eissn | 1366-5928 | |
dc.identifier.doi | 10.1080/00498254.2016.1230245 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 771 - 777 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | TAYLOR & FRANCIS LTD | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Pyrimidines | |
dc.subject | Aldehyde Oxidase | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Models, Molecular | |
dc.subject | Proton Magnetic Resonance Spectroscopy | |
dc.title | Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-25 | |
rioxxterms.versionofrecord | 10.1080/00498254.2016.1230245 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Xenobiotica; the fate of foreign compounds in biological systems | |
pubs.issue | 9 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.publication-status | Published | |
pubs.volume | 47 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Medicinal Chemistry 4 (including Analytical Chemistry) | |
dc.contributor.icrauthor | Liu, Manjuan | |
dc.contributor.icrauthor | Henley, Alan | |
dc.contributor.icrauthor | Le Bihan, Yann-Vai | |
dc.contributor.icrauthor | Bavetsias, Vassilios | |
dc.contributor.icrauthor | Raynaud, Florence | |