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  3. Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics

Structure-activity relationship study of prion inhibition by 2-aminopyridine-3,5-dicarbonitrile-based compounds: parallel synthesis, bioactivity, and in vitro pharmacokinetics

  • J Med Chem. 2007 Jan 11;50(1):65-73. doi: 10.1021/jm061045z.
Barnaby C H May 1,  Julie A Zorn,  Juanita Witkop,  John Sherrill,  Andrew C Wallace,  Giuseppe Legname,  Stanley B Prusiner,  Fred E Cohen
Affiliations

Affiliation

  • 1 Institute for Neurodegenerative Diseases, University of California-San Francisco, San Francisco, California 94158, USA. bmay@ind.ucsf.edu
PMID: 17201410 DOI: 10.1021/jm061045z
Abstract

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.

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