2-Aminothiazoles as therapeutic leads for prion diseases.

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.

• Authors: Alejandra Gallardo-Godoy, Joel Gever, Kimberly L Fife, B Michael Silber, Stanley B Prusiner, Adam R Renslo
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 4 Pg. 1010-21 (Feb 24 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21247166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• PrPSc Proteins
• Thiazoles

Topics

• Animals
• Biological Assay
• Brain (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Magnetic Resonance Spectroscopy
• Mice
• PrPSc Proteins (metabolism)
• Prion Diseases (drug therapy, metabolism, pathology)
• Spectrometry, Mass, Electrospray Ionization
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)