NR AVXP
AU May,B.C.H.; Zorn,J.A.; Witkop,J.; Sherrill,J.; Wallace,A.C.; Legname,G.; Prusiner,S.B.; Cohen,F.E.
TI Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics.
QU Journal of Medicinal Chemistry 2007 Jan 11; 50(1): 65-73
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB 2-Aminopyridine-3,5-dicarbonitrile compounds were previously identified as mimetics of dominant-negative prion protein mutants and inhibit prion replication in cultured cells. Here, we report findings from a comprehensive structure-activity relationship study of the 6-aminopyridine-3,5-dicarbonitrile scaffold. We identify compounds with significantly improved bioactivity (approximately 40-fold) against replication of the infectious prion isoform (PrPsc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.
MH Aminopyridines/*chemical synthesis/chemistry/pharmacology; Animals; Cell Line, Tumor; Combinatorial Chemistry Techniques; Membranes, Artificial; Mice; Models, Molecular; Nitriles/*chemical synthesis/chemistry/pharmacology; Permeability; PrPsc Proteins/*antagonists & inhibitors; Solubility; Structure-Activity Relationship
AD Institute for Neurodegenerative Diseases, University of California-San Francisco, San Francisco, California 94158, USA. bmay@ind.ucsf.edu
SP englisch
PO USA