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/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.
Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.