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

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May BC, Zorn JA, Witkop J, Sherrill J, Wallace AC, Legname G, Prusiner SB, Cohen FE

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.

PubMed ID

17201410 [ View in PubMed

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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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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Piclidenoson	Adenosine receptor A3	Ki (nM)	2	N/A	N/A	Details