2-aminothiazoles as therapeutic leads for prion diseases

Gallardo-Godoy, Alejandra, Gever, Joel, Fife, Kimberly L., Silber, B. Michael, Prusiner, Stanley B. and Renslo, Adam R. (2011) 2-aminothiazoles as therapeutic leads for prion diseases. Journal of Medicinal Chemistry, 54 4: 1010-1021. doi:10.1021/jm101250y


Author Gallardo-Godoy, Alejandra
Gever, Joel
Fife, Kimberly L.
Silber, B. Michael
Prusiner, Stanley B.
Renslo, Adam R.
Title 2-aminothiazoles as therapeutic leads for prion diseases
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2011-02
Sub-type Article (original research)
DOI 10.1021/jm101250y
Volume 54
Issue 4
Start page 1010
End page 1021
Total pages 12
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2011
Language eng
Formatted abstract
2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines (J. Virol. 2010, 84, 3408). We report here structure-activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining high drug concentrations in the brain. The results of this effort include the generation of informative structure-activity relationships (SAR) and the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC 50 of 0.94 μM in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of ∼25 μM in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases.
Keyword Neuroblastoma-Cells
Antiprion Compounds
Derivatives
Inhibition
Replication
Acridine
Design
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 58 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 68 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 01 Mar 2013, 13:45:39 EST by Susan Allen on behalf of Institute for Molecular Bioscience