Structure−Activity Relationship Study of Prion Inhibition by
2-Aminopyridine-3,5-dicarbonitrile-Based Compounds:  Parallel Synthesis, Bioactivity, and in
Vitro Pharmacokinetics

C. H. May, Barnaby; Zorn, Julie A.; Witkop, Juanita; Sherrill, John; Wallace, Andrew C.; Legname, Giuseppe; Prusiner, Stanley B.; Cohen, Fred E.

doi:10.1021/jm061045z.s001

jm061045z_si_001.pdf (100.18 kB)

Structure−Activity Relationship Study of Prion Inhibition by 2-Aminopyridine-3,5-dicarbonitrile-Based Compounds: Parallel Synthesis, Bioactivity, and in Vitro Pharmacokinetics

journal contribution

posted on 2007-01-11, 00:00 authored by Barnaby 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 (PrP^Sc) and suitable pharmacokinetic profiles to warrant evaluation in animal models of prion disease.