Evidence map›Paper›PMID 26224882›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2015

Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains.

Kurt Giles, David B Berry, Carlo Condello, Ronald C Hawley, Alejandra Gallardo-Godoy, Clifford Bryant, Abby Oehler, Manuel Elepano, Sumita Bhardwaj, Smita Patel and 5 more

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

Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
1.7field-weighted citation impact, top 17% 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

32 citing papers in PubMed, 56 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. New Therapeutic Modalities in Prion Diseases.Sub-cellular biochemistry · 2025
    Review
  6. Article
  7. Review
  8. Article
  9. Article
  10. Review
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. The role of prion strain diversity in the development of successful therapeutic treatments.Progress in molecular biology and translational science · 2020
    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

15 authors at 3 institutions in 2 countries.

Kurt GilesInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
David B BerryInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Carlo CondelloInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Ronald C HawleyInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Alejandra Gallardo-GodoyInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Clifford BryantInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Abby OehlerInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Manuel ElepanoInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Sumita BhardwajInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Smita PatelInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
B Michael SilberInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Shenheng GuanInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Stephen J DeArmondInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Adam R RensloInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco.
Stanley B PrusinerInstitute for Neurodegenerative Diseases (K.G., D.B.B., C.C., R.C.H., M.E., S.B., S.P., B.M.S., S.G., S.J.D., S.B.P); Small Molecule Discovery Center (A.G.-G., C.B., A.R.R.); and Departments of Neurology (K.G., C.C., R.C.H., B.M.S., S.B.P), Pharmaceutical Chemistry (A.G.-G., C.B., S.G., A.R.R.), Pathology (A.O., S.J.D.), Bioengineering and Therapeutic Sciences (B.M.S.), and Biochemistry and Biophysics (S.B.P.), University of California, San Francisco stanley.prusiner@ucsf.edu.
United States Nuclear Regulatory Commission · USDiscovery Centre · CAUniversity of California, San Francisco · US

Funding

VIRAL DEGENERATIVE DEMENTING DISEASE IN AGING (SUPP)P01AG002132 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SCHNIER, PAUL · 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
Identifying the Role of PrPSc Distribution & Other Proteins in Prion PathogenesisF32NS080630 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BERRY, DAVID B · 2013 to 2015
$159k
NIAID NIH HHS AI064709NIAID NIH HHS R01 AI064709NIA NIH HHS AG002132NIA NIH HHS AG010770NIA NIH HHS AG021601NIA NIH HHS AG031220NIA NIH HHS P01 AG002132NIA NIH HHS P01 AG010770NIA NIH HHS P01 AG021601NIA NIH HHS R37 AG031220NINDS NIH HHS F32 NS080630NINDS NIH HHS NS080630
6 · The paper itself

Abstract

Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich "scrapie" isoform (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions.

Indexed as

AnimalsBrainDose-Response Relationship, DrugFemaleHumansMicePrPSc ProteinsScrapieSpecies SpecificitySurvival AnalysisSurvival RateThiazolesTransgenesTreatment Outcome2-aminothiazolePrPSc ProteinsThiazoles

Identifiers

PMID26224882
PMCPMC4576665
OpenAlexW1901274455

What OpenQuestion holds

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Read underepoch 390

Registered trials

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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.