Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice
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- Silber, B.M., Rao, S., Fife, K.L. et al. Pharm Res (2013) 30: 932. doi:10.1007/s11095-012-0912-4
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To discover drugs lowering PrPSc 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.
We tested 2-AMT analogs for EC50 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/EC50 after dosing. We reasoned that compounds with high AUC/EC50 ratios should be good candidates going forward.
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/EC50 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.
IND24 and IND81 are active in vitro and show high AUC/EC50 ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease.
KEY WORDSantiprion drugs drug discovery IND24 IND81 prion disease
area under the drug concentration time curve
drug concentration after 3 days of dosing
clearance (total, intrinsic, hepatic, or otherwise)
maximum drug concentration
days postinoculation with prions
potency; drug concentration producing 50% of the maximal effect
fasted-state simulated intestinal fluid
Madin Darby canine kidney cells transfected with MDR1 gene
multidrug resistance protein 1, ATP-binding cassette sub-family B member 1
minimum inhibitory concentration
benign normally occurring prion protein on cell surface or inside cell
abnormal, misfolded, pathogenic form of PrPC
Rocky Mountain Laboratory
scrapie (RML)-infected neuroblastoma cells that overexpress PrPC
volume of distribution (steady-state or otherwise)