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

Atkinson, BN; Steadman, D; Mahy, W; Zhao, Y; Sipthorp, J; Bayle, ED; Svensson, F; ... Fish, PV; + view all (2019) Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors. Bioorganic & Medicinal Chemistry Letters , Article 126751. 10.1016/j.bmcl.2019.126751. (In press). Green open access

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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.

Type: Article
Title: Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bmcl.2019.126751
Publisher version: https://doi.org/10.1016/j.bmcl.2019.126751
Language: English
Additional information: © 2019 The Author(s). Published by Elsevier Ltd. Under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Notum inhibitor, Wnt signaling, CNS penetration, furano[23-d]pyrimidines, SBDD
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10084616
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