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

Silber B.M., Rao S., Fife K.L., Gallardo-Godoy A., Renslo A.R., Dalvie D.K., Giles K., Freyman Y., Elepano M., Gever J.R., Li Z., Jacobson M.P., Huang Y., Benet L.Z. and Prusiner S.B. (2013) Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice. Pharmaceutical Research, 30 4: 932-950. doi:10.1007/s11095-012-0912-4

Author Silber B.M.
Rao S.
Fife K.L.
Gallardo-Godoy A.
Renslo A.R.
Dalvie D.K.
Giles K.
Freyman Y.
Elepano M.
Gever J.R.
Li Z.
Jacobson M.P.
Huang Y.
Benet L.Z.
Prusiner S.B.
Title Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 0724-8741
Publication date 2013-02
Sub-type Article (original research)
DOI 10.1007/s11095-012-0912-4
Open Access Status
Volume 30
Issue 4
Start page 932
End page 950
Total pages 19
Place of publication New York United States
Publisher Springer New York LLC
Language eng
Formatted abstract
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.
Keyword Antiprion drugs
Drug discovery
Prion disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 18 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 16 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 04 Sep 2014, 12:01:33 EST by System User on behalf of Institute for Molecular Bioscience