Evidence map›Paper›PMID 31862412›Full record

ArticleBioorganic & medicinal chemistry letters2020

Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.

Benjamin N Atkinson, David Steadman, William Mahy, Yuguang Zhao, James Sipthorp, Elliott D Bayle, Fredrik Svensson, George Papageorgiou, Fiona Jeganathan, Sarah Frew and 4 more

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

Article in Bioorganic & medicinal chemistry letters, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
2.2field-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

7 citing papers in PubMed, 20 citations in OpenAlex.

  1. Article
  2. Coumarin-furo[2,3-RSC medicinal chemistry · 2024
    Article
  3. Article
  4. Article
  5. Structural Insights into Notum Covalent Inhibition.Journal of medicinal chemistry · 2021
    Article
  6. Review
  7. 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 4 institutions in 1 country.

Benjamin N AtkinsonAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
David SteadmanAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
William MahyAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
Yuguang ZhaoDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK.
James SipthorpAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK.
Elliott D BayleAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK.
Fredrik SvenssonAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK.
George PapageorgiouThe Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK.
Fiona JeganathanAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
Sarah FrewAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
Amy MonaghanAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
Magda BictashAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
E Yvonne JonesDivision of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK.
Paul V FishAlzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK. Electronic address: p.fish@ucl.ac.uk.
Alzheimer’s Research UK · GBThe Francis Crick Institute · GBUniversity College London · GBUniversity of Oxford · GB

Funding

Cancer Research UK 17721Cancer Research UK C375/A17721Cancer Research UK FC001002Medical Research Council FC001002Wellcome Trust 203141/Z/16/ZWellcome Trust FC001002
6 · The paper itself

Abstract

The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.

Indexed as

AcetylesteraseAmidesAnimalsBinding SitesCell Membrane PermeabilityCrystallography, X-RayDogsHalf-LifeInhibitory Concentration 50Madin Darby Canine Kidney CellsMaleMiceMice, Inbred C57BLMicrosomesMolecular Dynamics SimulationProtein Structure, TertiaryAcetylesteraseAmidespyrimidinePyrimidinesCNS penetrationFurano[2,3-d]pyrimidinesNotum inhibitorSBDDWnt signaling

Identifiers

PMID31862412
PMCPMC6961116
OpenAlexW2982474834

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.