Evidence map›Paper›PMID 27317802›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2016

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 and 2 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
2.1field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

20 citing papers in PubMed, 36 citations in OpenAlex.

  1. Article
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  4. Article
  5. Article
  6. Review
  7. Review
  8. Article
  9. Article
  10. Article
  11. Article
  12. Administration of FK506 from Late Stage of Disease Prolongs Survival of Human Prion-Inoculated Mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2020
    Article
  13. Article
  14. Immunotherapy against Prion Disease.Pathogens (Basel, Switzerland) · 2020
    Review
  15. Article
  16. Article
  17. Article
  18. Review
  19. Developing Therapeutics for PrP Prion Diseases.Cold Spring Harbor perspectives in medicine · 2017
    Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 1 institution in 1 country.

Kurt GilesInstitute 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.
David B BerryInstitute 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.
Carlo CondelloInstitute 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.
Brittany N DuggerInstitute 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.
Zhe LiInstitute 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.
Abby OehlerInstitute 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.
Sumita BhardwajInstitute 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.
Manuel ElepanoInstitute 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.
Shenheng GuanInstitute 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.
B Michael SilberInstitute 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.
Steven H OlsonInstitute 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.
Stanley B PrusinerInstitute 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 stanley.prusiner@ucsf.edu.
University of California, San Francisco · US

Funding

VIRAL DEGENERATIVE DEMENTING DISEASE IN AGING (SUPP)P01AG002132 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SALI, ANDREJ · 1985 to 2024
$51.7M
UNDERSTANDING AND IMPROVING SMALL MOLECULE INHIBITORS OF PRION REPLICATIONP01AG021601 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PRUSINER, STANLEY B · 2003 to 2013
$31.9M
SYNTHETIC AND RECOMBINANT PRP PEPTIDES AND PROTEINSP01AG010770 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PRUSINER, STANLEY B · 1993 to 2015
$30.3M
Towards Therapeutics for Neurodegenerative DiseasesR37AG031220 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PRUSINER, STANLEY B · 2008 to 2017
$6.2M
Preventing Human Prion Diseases - Inactivation of PrionsR01AI064709 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PRUSINER, STANLEY B · 2006 to 2010
$3.7M
NIAID NIH HHS R01 AI064709NIA NIH HHS P01 AG002132NIA NIH HHS P01 AG010770NIA NIH HHS P01 AG021601NIA NIH HHS R37 AG031220
6 · The paper itself

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.

Indexed as

Drug DiscoveryAmidesAnimalsBrainCreutzfeldt-Jakob SyndromeFemaleMicePrion DiseasesStructure-Activity RelationshipSurvival AnalysisAmides

Identifiers

PMID27317802
PMCPMC4998675
OpenAlexW2422768444

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.