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.
|Titolo:||Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics|
|Autori:||May, Bc; Zorn, Ja; Witkop, J; Sherrill, J; Wallace, Ac; Legname, Giuseppe; Prusiner, Sb; Cohen, Fe|
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||10.1021/jm061045z|
|Appare nelle tipologie:||1.1 Journal article|