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

DOI: 10.1016/j.bmcl.2019.126751 DOI Help

Authors: Benjamin N. Atkinson (UniversityAlzheimer’s Research UK UCL Drug Discovery Institute, University College London College London) , David Steadman (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , William Mahy (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Yuguang Zhao (Wellcome Centre for Human Genetics, University of Oxford) , James Sipthorp (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , Elliott D. Bayle (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , Fredrik Svensson (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London; The Francis Crick Institute) , George Papageorgiou (The Francis Crick Institute) , Fiona Jeganathan (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Sarah Frew (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Amy Monaghan (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , Magda Bictash (Alzheimer’s Research UK UCL Drug Discovery Institute, University College London) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Paul V. Fish (UK UCL Drug Discovery Institute, University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 14744

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.

Journal Keywords: Notum inhibitor; Wnt signaling; CNS penetrationfurano[23-d]pyrimidines; SBDD

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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