2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease

Li Z., Silber B.M., Rao S., Gever J.R., Bryant C., Gallardo-Godoy A., Dolghih E., Widjaja K., Elepano M., Jacobson M.P., Prusiner S.B. and Renslo A.R. (2013) 2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease. ChemMedChem, 8 5: 847-857. doi:10.1002/cmdc.201300007


Author Li Z.
Silber B.M.
Rao S.
Gever J.R.
Bryant C.
Gallardo-Godoy A.
Dolghih E.
Widjaja K.
Elepano M.
Jacobson M.P.
Prusiner S.B.
Renslo A.R.
Title 2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease
Journal name ChemMedChem   Check publisher's open access policy
ISSN 1860-7179
1860-7187
Publication date 2013-05
Sub-type Article (original research)
DOI 10.1002/cmdc.201300007
Open Access Status
Volume 8
Issue 5
Start page 847
End page 857
Total pages 11
Place of publication Weinheim Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Language eng
Formatted abstract
Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40%, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrPSc. Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.
Keyword 2-aminothiazoles
Neurological agents
Pharmacokinetic optimization
Prion disease
Structure-activity relationships
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
 
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 11 times in Scopus Article | Citations
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