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Research ArticleDrug Discovery and Translational Medicine

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Kurt Giles, David B. Berry, Carlo Condello, Brittany N. Dugger, Zhe Li, Abby Oehler, Sumita Bhardwaj, Manuel Elepano, Shenheng Guan, B. Michael Silber, Steven H. Olson and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 537-547; DOI: https://doi.org/10.1124/jpet.116.235556
Kurt Giles
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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David B. Berry
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Carlo Condello
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Brittany N. Dugger
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Zhe Li
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Abby Oehler
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Sumita Bhardwaj
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Manuel Elepano
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Shenheng Guan
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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B. Michael Silber
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Steven H. Olson
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Stanley B. Prusiner
Institute for Neurodegenerative Diseases (K.G., D.B.B., C.C., B.N.D., Z.L., A.O., S.B., M.E., S.G., B.M.S., S.H.O., S.B.P.) and Departments of Neurology (K.G., C.C., B.N.D., Z.L., B.M.S., S.H.O., S.B.P.), Pharmaceutical Chemistry (S.G.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco, California
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Abstract

Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure–activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.

Footnotes

    • Received June 1, 2016.
    • Accepted June 16, 2016.
  • ↵1 Current affiliation: Global Blood Therapeutics, South San Francisco, California.

  • ↵2 Current affiliation: Reiley Pharmaceuticals, Inc., San Francisco, California.

  • This work was supported by the National Institutes of Health National Institute on Aging [Grants AI064709, AG002132, AG010770, AG021601, and AG031220] and by gifts from the Sherman Fairchild Foundation, the Rainwater Charitable Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation.

  • dx.doi.org/10.1124/jpet.116.235556.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleDrug Discovery and Translational Medicine

Aryl Amides as Anti-prion Therapeutics

Kurt Giles, David B. Berry, Carlo Condello, Brittany N. Dugger, Zhe Li, Abby Oehler, Sumita Bhardwaj, Manuel Elepano, Shenheng Guan, B. Michael Silber, Steven H. Olson and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 537-547; DOI: https://doi.org/10.1124/jpet.116.235556

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Research ArticleDrug Discovery and Translational Medicine

Aryl Amides as Anti-prion Therapeutics

Kurt Giles, David B. Berry, Carlo Condello, Brittany N. Dugger, Zhe Li, Abby Oehler, Sumita Bhardwaj, Manuel Elepano, Shenheng Guan, B. Michael Silber, Steven H. Olson and Stanley B. Prusiner
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 537-547; DOI: https://doi.org/10.1124/jpet.116.235556
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