2-Aminothiazoles as therapeutic leads for prion diseases.
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 EC(50) 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.
The Small Molecule Discovery Center, San Francisco, California 94158, United States.
Alejandra
A
Gallardo-Godoy
Joel
J
Gever
Kimberly L
KL
Fife
B Michael
BM
Silber
Stanley B
SB
Prusiner
Adam R
AR
Renslo
D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D018620:PrPSc Proteins; D013844:Thiazoles
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