Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 43, Issue 1, Pages 93-106Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2007.02.018
Keywords
prion protein; TSE; vCJD; pyridine dicarbonitriles; microwave irradiation; SPR
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Funding
- Biotechnology and Biological Sciences Research Council [BB/E014119/1] Funding Source: Medline
- BBSRC [BB/E014119/1] Funding Source: UKRI
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We report the preparation and screening of a set of 55 pyridine dicarbonitriles as potential prion disease therapeutics. Use of microwave irradiation in an attempt to improve the synthesis typically led to only small enhancement in yields but gave cleaner reactions facilitating product isolation. The library was analysed for binding to human prion protein (huPrP(C)) by surface plasmon resonance and for inhibition of the formation of its partially protease resistant isoform PrPSc in mouse brain cells (SMB). A total of 26 compounds were found to bind to huPrP(C) whilst 12 showed discernable inhibition of PrPSc formation, five displaying EC50S in the range 2.5-9 mu M. Two compounds were found to reduce PrPSc levels to below 30% relative to an untreated control at 50 nM. (C) 2007 Elsevier Masson SAS. All rights reserved.
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