2‐Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease. Issue 5 (18th March 2013)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: ChemMedChem. Volume 8:Issue 5(2013:May)
• Page Start: 847
• Page End: 857
• Publication Date: 2013-03-18
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300007
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Recently, we described the aminothiazole lead (4‐biphenyl‐4‐ylthiazol‐2‐yl)‐(6‐methylpyridin‐2‐yl)‐amine (<bold>1</bold>), 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 <bold>1</bold> exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease‐causing prion protein PrP^Sc. Accordingly, we sought to identify analogues of <bold>1</bold> 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 <bold>1</bold>.</p> </abstract>