Evidence map›Paper›PMID 31320211›Full record

ArticleBioorganic & medicinal chemistry2019

The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability.

Disha M Gandhi, Ricardo Rosas, Eric Greve, Kaitlin Kentala, N'Guessan D-R Diby, Vladyslava A Snyder, Allison Stephans, Teresa H W Yeung, Saravanan Subramaniam, Elliot DiMilo and 4 more

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

Article in Bioorganic & medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
0.5field-weighted citation impact, top 36% 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

11 citing papers in PubMed, 16 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Review
  9. Review
  10. Review
  11. 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

14 authors at 3 institutions in 1 country.

Disha M GandhiDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Ricardo RosasDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Eric GreveDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Kaitlin KentalaDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
N'Guessan D-R DibyDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Vladyslava A SnyderDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Allison StephansDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Teresa H W YeungDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Saravanan SubramaniamBlood Research Institute, Versiti, Milwaukee, WI 53226, USA.
Elliot DiMiloDepartment of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
Khia E KurtenbachDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Leggy A ArnoldDepartment of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
Hartmut WeilerBlood Research Institute, Versiti, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Chris DockendorffDepartment of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: christopher.dockendorff@mu.edu.
Marquette University · USUniversity of Wisconsin–Milwaukee · USVersiti Blood Center of Wisconsin · US

Funding

Regulation of Innate Immunity by Coagulation ReceptorsR01HL133348 · NHLBI · VERSITI WISCONSIN, INC. · PI WEILER, HARTMUT KARL-HEINZ · 2016 to 2019
$1.7M
Protein C pathway function in hematopoiesisR01HL117132 · NHLBI · VERSITI WISCONSIN, INC. · PI WEILER, HARTMUT KARL-HEINZ · 2014 to 2017
$1.7M
Novel Approaches to the Modulation of Protease-Activated Receptor (PAR) SignalingR15HL127636 · NHLBI · MARQUETTE UNIVERSITY · PI DOCKENDORFF, CHRISTOPHER · 2015 to 2020
$903k
NHLBI NIH HHS R01 HL117132NHLBI NIH HHS R01 HL133348NHLBI NIH HHS R15 HL127636
6 · The paper itself

Abstract

Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.

Indexed as

Platelet Aggregation InhibitorsAllosteric RegulationAnti-Inflammatory Agents, Non-SteroidalDose-Response Relationship, DrugDrug StabilityHumansLigandsMolecular StructureOxazolesPlatelet AggregationReceptor, PAR-1Signal TransductionStructure-Activity RelationshipAnti-Inflammatory Agents, Non-SteroidalLigandsOxazolesPlatelet Aggregation InhibitorsReceptor, PAR-1Allosteric inhibitorAnti-inflammatoryAnti-plateletAntithromboticBiased ligandML161NRD-21OxazolePAR1Parmodulin

Identifiers

PMID31320211
PMCPMC6706283
OpenAlexW2955142293

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.