AI Article Synopsis
- The study aims to find drugs that reduce prion protein levels in infected neuronal cells, targeting their effective use in mouse models and potential treatment for humans with prion diseases.
- Researchers tested various 2-AMT analogs for their effectiveness (EC50) and how well they are absorbed in the brain after different doses.
- From the 27 compounds assessed, IND24 and IND81 showed promising results for brain concentration and favorable absorption profiles, leading to their selection for further testing in mouse models of prion disease.
Article 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 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/EC50 ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640342 | PMC |
| http://dx.doi.org/10.1007/s11095-012-0912-4 | DOI Listing |
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