2-Aminothiazoles as Therapeutic Leads for Prion Diseases

• Published in: Journal of medicinal chemistry Vol. 54; no. 4; pp. 1010 - 1021
• Main Authors: Gallardo-Godoy, Alejandra, Gever, Joel, Fife, Kimberly L, Silber, B. Michael, Prusiner, Stanley B, Renslo, Adam R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.02.2011; Amer Chemical Soc
• Subjects: Animals; Biological Assay; Brain - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mice; Pharmacology & Pharmacy; Prion Diseases - drug therapy; Prion Diseases - metabolism; Prion Diseases - pathology; PrPSc Proteins - metabolism; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; ANTIPRION COMPOUNDS; DESIGN; INHIBITION; REPLICATION; ACRIDINE; NEUROBLASTOMA-CELLS; DERIVATIVES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101250y

2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines ( J. Virol. 2010, 84, 3408 ). We report here structure−activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining high drug concentrations in the brain. The results of this effort include the generation of informative structure−activity relationships (SAR) and the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC50 of 0.94 μM in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of ∼25 μM in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases.