Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice.

ABSTRACT:

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 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.

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/EC50 ratios after

SUBMITTER: Silber BM 

PROVIDER: S-EPMC3640342 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature