Targeted Fluorination of a Non-steroidal Anti-inflammatory Drug to Prolong Metabolic Half-life

DC FieldValueLanguage
dc.contributor.authorShaughnessy, Maxwell J.-
dc.contributor.authorHarsanyi, Antal-
dc.contributor.authorLi, Jingji-
dc.contributor.authorBright, Tara V.-
dc.contributor.authorMurphy, Cormac D.-
dc.contributor.authorSandford, Graham-
dc.date.accessioned2015-08-11T09:26:49Z-
dc.date.available2015-08-11T09:26:49Z-
dc.date.copyright2014 Wileyen
dc.date.issued2014-04-
dc.identifier.citationChemMedChemen
dc.identifier.urihttp://hdl.handle.net/10197/6759-
dc.description.abstractIn drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug’s metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4′-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.en
dc.language.isoenen
dc.publisherWileyen
dc.rightsThis is the author's version of the following article: Maxwell J. Shaughnessy, Antal Harsanyi, Jingji Li, Tara Bright, Dr. Cormac D. Murphy, andProf. Graham Sandford (2014) "Targeted Fluorination of a Non-steroidal Anti-inflammatory Drug to Prolong Metabolic Half-life" ChemMedChem, 9(4) : 733-736 which has been published in final form at http://dx.doi.org/10.1002/cmdc.201300490en
dc.subjectCross-coupling reactionsen
dc.subjectCytochrome P450sen
dc.subjectDrug designen
dc.subjectFluorineen
dc.subjectDrug metabolismen
dc.titleTargeted Fluorination of a Non-steroidal Anti-inflammatory Drug to Prolong Metabolic Half-lifeen
dc.typeJournal Articleen
dc.internal.authorcontactothercormac.d.murphy@ucd.ie-
dc.statusPeer revieweden
dc.identifier.volume9en
dc.identifier.issue4en
dc.identifier.startpage733en
dc.identifier.endpage736en
dc.identifier.doi10.1002/cmdc.201300490-
dc.neeo.contributorShaughnessy|Maxwell J.|aut|-
dc.neeo.contributorHarsanyi|Antal|aut|-
dc.neeo.contributorLi|Jingji|aut|-
dc.neeo.contributorBright|Tara V.|aut|-
dc.neeo.contributorMurphy|Cormac D.|aut|-
dc.neeo.contributorSandford|Graham|aut|-
dc.description.othersponsorshipRoyal Society Travel Granten
dc.internal.rmsid377886986-
dc.date.updated2015-06-02T09:22:15Z-
item.grantfulltextopen-
item.fulltextWith Fulltext-
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