title: Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice.
abstract: OBJECTIVE
  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.
authors: Institute for Neurodegenerative Diseases, University of California, San Francisco, California, USA.
authors: B Michael
authors: BM
authors: Silber
authors: Satish
authors: S
authors: Rao
authors: Kimberly L
authors: KL
authors: Fife
authors: Alejandra
authors: A
authors: Gallardo-Godoy
authors: Adam R
authors: AR
authors: Renslo
authors: Deepak K
authors: DK
authors: Dalvie
authors: Kurt
authors: K
authors: Giles
authors: Yevgeniy
authors: Y
authors: Freyman
authors: Manuel
authors: M
authors: Elepano
authors: Joel R
authors: JR
authors: Gever
authors: Zhe
authors: Z
authors: Li
authors: Matthew P
authors: MP
authors: Jacobson
authors: Yong
authors: Y
authors: Huang
authors: Leslie Z
authors: LZ
authors: Benet
authors: Stanley B
authors: SB
authors: Prusiner
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy*; D020033:Protein Isoforms / Q000378:metabolism; D012995:Solubility; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018620:PrPSc Proteins; D020033:Protein Isoforms; D013844:Thiazoles; C004483:2-aminothiazole; D003577:Cytochrome P-450 Enzyme System