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ChemMedChem. 2013 May;8(5):847-57. doi: 10.1002/cmdc.201300007. Epub 2013 Mar 18.

2-Aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease.

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1
Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143, USA.

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 PrP(Sc) . 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.

PMID:
23509039
PMCID:
PMC3984044
DOI:
10.1002/cmdc.201300007
[Indexed for MEDLINE]
Free PMC Article
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