Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice

PURPOSE: To discover drugs lowering PrP(Sc) in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases. METHODS: We tested 2-AMT analogs for EC(50) and PK after a 40 mg/kg single dose and 40–210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC(50) after dosing. We reasoned that compounds with high AUC/EC(50) ratios should be good candidates going forward. RESULTS: We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27–40%. AUC/EC(50) ratios after 3 days were >100 (total) and 48–113 (unbound). Stability in liver microsomes ranged from 30–>60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter. CONCLUSIONS: IND24 and IND81 are active in vitro and show high AUC/EC(50) ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease