Structure−Activity Relationship Study of Prion Inhibition by
2-Aminopyridine-3,5-dicarbonitrile-Based Compounds: Parallel Synthesis, Bioactivity, and in
Vitro Pharmacokinetics
posted on 2007-01-11, 00:00authored byBarnaby C. H. May, Julie A. Zorn, Juanita Witkop, John Sherrill, Andrew C. Wallace, Giuseppe Legname, Stanley B. Prusiner, Fred E. Cohen
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.