Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics.
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.
May
Barnaby C H
BC
Institute for Neurodegenerative Diseases, University of California-San Francisco, San Francisco, California 94158, USA. bmay@ind.ucsf.edu
Zorn
Julie A
JA
Witkop
Juanita
J
Sherrill
John
J
Wallace
Andrew C
AC
Legname
Giuseppe
G
Prusiner
Stanley B
SB
Cohen
Fred E
FE
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D008567:Membranes, Artificial; D009570:Nitriles; D018620:PrPSc Proteins