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dc.contributor.authorReddy, Tummala Rama Krishna
dc.contributor.authorMutter, Roger
dc.contributor.authorHeal, William
dc.contributor.authorGuo, Kai
dc.contributor.authorGillet, Valerie J.
dc.contributor.authorPratt , Steven
dc.contributor.authorChen, Beining
dc.date.accessioned2013-04-09T08:59:38Z
dc.date.available2013-04-09T08:59:38Z
dc.date.issued2006
dc.identifier.citationReddy , T R K , Mutter , R , Heal , W , Guo , K , Gillet , V J , Pratt , S & Chen , B 2006 , ' Library Design, Synthesis and Screening : Pyridine Dicarbonitriles as Potential Prion Disease Therapeutics ' , Journal of Medicinal Chemistry , vol. 49 , no. 2 , pp. 607-615 . https://doi.org/10.1021/jm050610f
dc.identifier.issn0022-2623
dc.identifier.otherPURE: 1375050
dc.identifier.otherPURE UUID: 7c6d1385-7e4c-4e26-b095-420037b991f4
dc.identifier.otherScopus: 31544475731
dc.identifier.urihttp://hdl.handle.net/2299/10343
dc.descriptionThis research project was supported by the Department of Health UK
dc.description.abstractTransmissible spongiform encephalopathies (TSEs) or prion diseases are a family of invariably fatal neurodegenerative disorders, and there are no effective therapeutics currently available. In this paper, we report on the design, synthesis, and screening of a series of pyridine dicarbonitriles as potential novel prion disease therapeutics. A virtual reaction-based library of 1050 compounds was constructed. Docking and evaluation using GOLD scores assisted the initial selection of compounds for synthesis. The selection was augmented with further compounds to increase structural diversity. A total of 45 compounds were synthesized via a one-pot three-component coupling reaction. The mechanism of the three-component coupling reaction was investigated, and it was discovered that chemical oxidation is required for the last step, forming the pyridine ring (aromatization). A total of 19 compounds were identified as binders to one or more forms of prion protein by in vitro screening using surface plasmon resonance (SPR). A selection of compounds were investigated for activity in cells, resulting in the discovery of a new inhibitor of PrPSc formationen
dc.language.isoeng
dc.relation.ispartofJournal of Medicinal Chemistry
dc.titleLibrary Design, Synthesis and Screening : Pyridine Dicarbonitriles as Potential Prion Disease Therapeuticsen
dc.contributor.institutionDepartment of Pharmacy
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.contributor.institutionMedicinal and Analytical Chemistry
dc.description.statusPeer reviewed
dc.relation.school
dcterms.dateAccepted2006
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1021/jm050610f
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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