Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice
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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.
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- Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice
Volume 30, Issue 4 , pp 932-950
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- antiprion drugs
- drug discovery
- prion disease
- Industry Sectors
- B. Michael Silber (1) (2) (3)
- Satish Rao (1) (2)
- Kimberly L. Fife (1) (3)
- Alejandra Gallardo-Godoy (4)
- Adam R. Renslo (4) (5)
- Deepak K. Dalvie (6)
- Kurt Giles (1) (2)
- Yevgeniy Freyman (1)
- Manuel Elepano (1)
- Joel R. Gever (1) (2)
- Zhe Li (1) (2) (3)
- Matthew P. Jacobson (5)
- Yong Huang (3)
- Leslie Z. Benet (3)
- Stanley B. Prusiner (1) (2) (7)
- Author Affiliations
- 1. Institute for Neurodegenerative Diseases, University of California, San Francisco, California, USA
- 2. Department of Neurology, University of California, San Francisco, California, USA
- 3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- 4. Small Molecule Discovery Center, University of California, San Francisco, California, USA
- 5. Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
- 6. Pfizer Global Research & Development, La Jolla, California, USA
- 7. 675 Nelson Rising Ln, Room 318, San Francisco, California, 94143-0518, USA