Pharmaceutical Research

, Volume 30, Issue 4, pp 932–950

Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice

  • B. Michael Silber
  • Satish Rao
  • Kimberly L. Fife
  • Alejandra Gallardo-Godoy
  • Adam R. Renslo
  • Deepak K. Dalvie
  • Kurt Giles
  • Yevgeniy Freyman
  • Manuel Elepano
  • Joel R. Gever
  • Zhe Li
  • Matthew P. Jacobson
  • Yong Huang
  • Leslie Z. Benet
  • Stanley B. Prusiner
Research Paper

DOI: 10.1007/s11095-012-0912-4

Cite this article as:
Silber, B.M., Rao, S., Fife, K.L. et al. Pharm Res (2013) 30: 932. doi:10.1007/s11095-012-0912-4

Abstract

Purpose

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.

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.

KEY WORDS

antiprion drugs drug discovery IND24 IND81 prion disease 

Abbreviations

2-AMT

2-aminothiazole scaffold

AUC

area under the drug concentration time curve

C3-day

drug concentration after 3 days of dosing

CJD

Creutzfeldt-Jakob disease

Cl

clearance (total, intrinsic, hepatic, or otherwise)

Cmax

maximum drug concentration

dpi

days postinoculation with prions

EC50

potency; drug concentration producing 50% of the maximal effect

FaSSIF

fasted-state simulated intestinal fluid

HTS

high-throughput screening

IV

intravenous

MDCK-MDR1

Madin Darby canine kidney cells transfected with MDR1 gene

MDR1

multidrug resistance protein 1, ATP-binding cassette sub-family B member 1

MIC

minimum inhibitory concentration

P-gp

p-glycoprotein

PK

pharmacokinetics

PO

oral

PrPC

benign normally occurring prion protein on cell surface or inside cell

PrPSc

abnormal, misfolded, pathogenic form of PrPC

RML

Rocky Mountain Laboratory

SAR

structure-activity relationship

ScN2a-cl3

scrapie (RML)-infected neuroblastoma cells that overexpress PrPC

V

volume of distribution (steady-state or otherwise)

Supplementary material

11095_2012_912_MOESM1_ESM.doc (97 kb)
ESM 1(DOC 97 kb)

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • 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
  1. 1.Institute for Neurodegenerative DiseasesUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of Bioengineering and Therapeutic SciencesUniversity of CaliforniaSan FranciscoUSA
  4. 4.Small Molecule Discovery CenterUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Pharmaceutical ChemistryUniversity of CaliforniaSan FranciscoUSA
  6. 6.Pfizer Global Research & DevelopmentLa JollaUSA
  7. 7.San FranciscoUSA

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