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Research ArticleDrug Discovery and Translational Medicine

Biaryl Amides and Hydrazones as Therapeutics for Prion Disease in Transgenic Mice

Duo Lu, Kurt Giles, Zhe Li, Satish Rao, Elena Dolghih, Joel R. Gever, Michal Geva, Manuel L. Elepano, Abby Oehler, Clifford Bryant, Adam R. Renslo, Matthew P. Jacobson, Stephen J. DeArmond, B. Michael Silber and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics November 2013, 347 (2) 325-338; DOI: https://doi.org/10.1124/jpet.113.205799
Duo Lu
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Kurt Giles
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Zhe Li
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Satish Rao
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Elena Dolghih
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Joel R. Gever
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Michal Geva
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Manuel L. Elepano
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Abby Oehler
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Clifford Bryant
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Adam R. Renslo
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Matthew P. Jacobson
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Stephen J. DeArmond
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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B. Michael Silber
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Stanley B. Prusiner
Institute for Neurodegenerative Diseases (D.L., K.G., Z.L., S.R., J.R.G., M.G., M.L.E., S.J.D., B.M.S., S.B.P.), Department of Neurology (K.G., Z.L., S.R., J.R.G., B.M.S., S.B.P.), Department of Pathology (A.O., S.J.D.), Department of Pharmaceutical Chemistry (E.D., C.B., A.R.R., M.P.J.), Department of Bioengineering and Therapeutic Sciences (B.M.S.), and Small Molecule Discovery Center (C.B., A.R.R.), University of California, San Francisco, California
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Abstract

The only small-molecule compound demonstrated to substantially extend survival in prion-infected mice is a biaryl hydrazone termed “Compd B” (4-pyridinecarboxaldehyde,2-[4-(5-oxazolyl)phenyl]hydrazone). However, the hydrazone moiety of Compd B results in toxic metabolites, making it a poor candidate for further drug development. We developed a pharmacophore model based on diverse antiprion compounds identified by high-throughput screening; based on this model, we generated biaryl amide analogs of Compd B. Medicinal chemistry optimization led to multiple compounds with increased potency, increased brain concentrations, and greater metabolic stability, indicating that they could be promising candidates for antiprion therapy. Replacing the pyridyl ring of Compd B with a phenyl group containing an electron-donating substituent increased potency, while adding an aryl group to the oxazole moiety increased metabolic stability. To test the efficacy of Compd B, we applied bioluminescence imaging (BLI), which was previously shown to detect prion disease onset in live mice earlier than clinical signs. In our studies, Compd B showed good efficacy in two lines of transgenic mice infected with the mouse-adapted Rocky Mountain Laboratory (RML) strain of prions, but not in transgenic mice infected with human prions. The BLI system successfully predicted the efficacies in all cases long before extension in survival could be observed. Our studies suggest that this BLI system has good potential to be applied in future antiprion drug efficacy studies.

Footnotes

    • Received April 23, 2013.
    • Accepted August 20, 2013.
  • ↵1 Current affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.

  • ↵2 Current affiliation: Global Blood Therapeutics, Inc., South San Francisco, California.

  • ↵3 Current affiliation: Endocyte, Inc., West Lafayette, Indiana

  • ↵4 Current affiliation: Teva Pharmaceuticals, Netanya, Israel.

  • ↵5 Current affiliation: ELMEDTECH, LLC, San Francisco, California.

  • D.L. and K.G. contributed equally to this work.

  • This work was supported by the National Institutes of Health National Institute on Aging [Grants AI064709, AG002132, AG010770, and AG021601]; by gifts from the Sherman Fairchild Foundation and Rainwater Charitable Foundation; and by a gift from the G. Harold and Leila Y. Mathers Charitable Foundation.

  • dx.doi.org/10.1124/jpet.113.205799.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 2
1 Nov 2013
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Research ArticleDrug Discovery and Translational Medicine

Prion Therapeutics and Bioluminescence Imaging

Duo Lu, Kurt Giles, Zhe Li, Satish Rao, Elena Dolghih, Joel R. Gever, Michal Geva, Manuel L. Elepano, Abby Oehler, Clifford Bryant, Adam R. Renslo, Matthew P. Jacobson, Stephen J. DeArmond, B. Michael Silber and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 325-338; DOI: https://doi.org/10.1124/jpet.113.205799

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Research ArticleDrug Discovery and Translational Medicine

Prion Therapeutics and Bioluminescence Imaging

Duo Lu, Kurt Giles, Zhe Li, Satish Rao, Elena Dolghih, Joel R. Gever, Michal Geva, Manuel L. Elepano, Abby Oehler, Clifford Bryant, Adam R. Renslo, Matthew P. Jacobson, Stephen J. DeArmond, B. Michael Silber and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics November 1, 2013, 347 (2) 325-338; DOI: https://doi.org/10.1124/jpet.113.205799
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