Evidence map›Paper›PMID 34855359›Full record

ArticleACS chemical neuroscience2021

Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Jeanette L Bertron, Matthew T Duvernay, Sidnee G Mitchell, Shannon T Smith, Jae G Maeng, Anna L Blobaum, Dexter C Davis, Jens Meiler, Heidi E Hamm, Craig W Lindsley

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

Article in ACS chemical neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.3field-weighted citation impact, top 41% 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

2 citing papers in PubMed, 4 citations in OpenAlex.

  1. Article
  2. 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

10 authors at 1 institution in 2 countries.

Jeanette L BertronDepartment of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
Matthew T DuvernayDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Sidnee G MitchellDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Shannon T SmithChemical and Physical Biology Program, Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Jae G MaengDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Anna L BlobaumDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Dexter C DavisDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Jens MeilerDepartment of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
Heidi E HammDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
Craig W LindsleyDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.ORCID 0000-0003-0168-1445
Vanderbilt University · US

Funding

Targeting PAR4 in Thrombotic Disorders:Pharmacogenomic ApproachR01HL133923 · NHLBI · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E · 2017 to 2020
$2.3M
Cerebrovascular involvement in Alzheimer's Disease: PAR4 AntagonismRF1AG068623 · NIA · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E, MEILER, JENS · 2021 to 2021
$2.2M
Cerebrovascular involvement in Alzheimer's Disease: PAR4 AntagonismR01AG068623 · NIA · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E, MEILER, JENS · 2024 to 2025
$1.4M
High-Performance Computer Cluster for Biomedical ResearchS10OD023680 · OD · VANDERBILT UNIVERSITY · PI MEILER, JENS · 2017 to 2017
$587k
Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementiaR21AG073891 · NIA · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E · 2021 to 2022
$462k
Hybrid Methods for Prediction and Design of Novel Human Influenza AntibodiesR56AI110750 · NIAID · VANDERBILT UNIVERSITY · PI CROWE, JAMES E, MEILER, JENS · 2014 to 2014
$433k
Hybridized structure- and ligand- based drug discovery approaches targeting ASCT2, an amino acid transporter critical for upregulated cell proliferation in numerous cancer typesF31CA243353 · NCI · VANDERBILT UNIVERSITY · PI SMITH, SHANNON TALLI · 2019 to 2022
$106k
NHLBI NIH HHS R01 HL133923NIAID NIH HHS R56 AI110750NIA NIH HHS R01 AG068623NIA NIH HHS R21 AG073891NIA NIH HHS RF1 AG068623NIH HHS S10 OD023680
6 · The paper itself

Abstract

The detailed pharmacology and therapeutic potential of the central PAR4 receptors are poorly understood due to a lack of potent, selective, and brain-penetrant tool compounds. Despite this, robust data with biochemical and genetic tools show the therapeutic potential of PAR4 antagonists in traumatic brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders with a neuroinflammatory component. Thus, we performed a functional HTS campaign, identified a fundamentally new PAR4 competitive inhibitor chemotype, optimized this new series (increased potency >45-fold), discovered enantiospecific activity (though opposing preference for human versus mouse PAR4), and engendered high central nervous system penetration (rat

Indexed as

Central Nervous SystemReceptors, ThrombinAnimalsBrainMiceRatsprotease-activated receptor 4Receptors, ThrombinCNS penetrantPAR4protease-activated receptorSARselectivity

Identifiers

PMID34855359
PMCPMC8823334
OpenAlexW3215880393

What OpenQuestion holds

Textmetadata
LicenceTDM
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.