1448015-78-8Relevant articles and documents
2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease
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.
, p. 847 - 857 (2013/08/25)
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.
