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2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease

Authors

  • Prof. Dr. Zhe Li,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Prof. Dr. B. Michael Silber,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA)
    3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143 (USA)
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    • Current address: ELMEDTECH, San Francisco, CA 94123 (USA)

  • Prof. Dr. Satish Rao,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Prof. Dr. Joel R. Gever,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Clifford Bryant,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Dr. Alejandra Gallardo-Godoy,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Dr. Elena Dolghih,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Kartika Widjaja,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Manuel Elepano,

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Prof. Dr. Matthew P. Jacobson,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Prof. Dr. Stanley B. Prusiner,

    Corresponding author
    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Neurology, University of California, San Francisco, San Francisco, CA 94143 (USA)
    • Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
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  • Prof. Dr. Adam R. Renslo

    1. Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94143 (USA)
    2. Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, San Francisco, CA 94143 (USA)
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Abstract

Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40 %, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrPSc. Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.

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