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Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.
Atkinson, Benjamin N; Steadman, David; Mahy, William; Zhao, Yuguang; Sipthorp, James; Bayle, Elliott D; Svensson, Fredrik; Papageorgiou, George; Jeganathan, Fiona; Frew, Sarah; Monaghan, Amy; Bictash, Magda; Jones, E Yvonne; Fish, Paul V.
Afiliação
  • Atkinson BN; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Steadman D; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Mahy W; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Zhao Y; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK.
  • Sipthorp J; Alzheimer'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.
  • Bayle ED; Alzheimer'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.
  • Svensson F; Alzheimer'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.
  • Papageorgiou G; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, UK.
  • Jeganathan F; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Frew S; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Monaghan A; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Bictash M; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK.
  • Jones EY; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK.
  • Fish PV; Alzheimer'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.
Bioorg Med Chem Lett ; 30(3): 126751, 2020 02 01.
Article em En | MEDLINE | ID: mdl-31862412
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Acetilesterase / Amidas Limite: Animals Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Acetilesterase / Amidas Limite: Animals Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Reino Unido