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dc.contributor.authorHayes, A
dc.contributor.authorMok, NY
dc.contributor.authorLiu, M
dc.contributor.authorThai, C
dc.contributor.authorHenley, AT
dc.contributor.authorAtrash, B
dc.contributor.authorLanigan, RM
dc.contributor.authorSejberg, J
dc.contributor.authorLe Bihan, Y-V
dc.contributor.authorBavetsias, V
dc.contributor.authorBlagg, J
dc.contributor.authorRaynaud, FI
dc.date.accessioned2017-09-19T08:52:12Z
dc.date.issued2017-09
dc.identifier.citationXenobiotica; the fate of foreign compounds in biological systems, 2017, 47 (9), pp. 771 - 777
dc.identifier.issn0049-8254
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/831
dc.identifier.eissn1366-5928
dc.identifier.doi10.1080/00498254.2016.1230245
dc.description.abstract1. 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.
dc.formatPrint-Electronic
dc.format.extent771 - 777
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectPyrimidines
dc.subjectAldehyde Oxidase
dc.subjectStructure-Activity Relationship
dc.subjectModels, Molecular
dc.subjectProton Magnetic Resonance Spectroscopy
dc.titlePyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
dc.typeJournal Article
dcterms.dateAccepted2016-08-25
rioxxterms.versionofrecord10.1080/00498254.2016.1230245
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfXenobiotica; the fate of foreign compounds in biological systems
pubs.issue9
pubs.notesNo 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-statusPublished
pubs.volume47
pubs.embargo.termsNo embargo
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamMedicinal Chemistry 4 (including Analytical Chemistry)en_US
dc.contributor.icrauthorBavetsias, Vassiliosen
dc.contributor.icrauthorMok, Ngaien
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorHenley, Alanen
dc.contributor.icrauthorLiu, Manjuanen


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