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

  • Author(s): Li, Zhe
  • Silber, B Michael
  • Rao, Satish
  • Gever, Joel R
  • Bryant, Clifford
  • Gallardo-Godoy, Alejandra
  • Dolghih, Elena
  • Widjaja, Kartika
  • Elepano, Manuel
  • Jacobson, Matthew P
  • Prusiner, Stanley B
  • Renslo, Adam R
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984044/
No data is associated with this publication.
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.

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