The Francis Crick Institute
1-s2.0-S0960894X19307140-main.pdf (1.11 MB)

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

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journal contribution
posted on 2020-10-22, 13:56 authored by Benjamin N Atkinson, David Steadman, William Mahy, Yuguang Zhao, James Sipthorp, Elliott D Bayle, Fredrik Svensson, George Papageorgiou, Fiona Jeganathan, Sarah Frew, Amy Monaghan, Magda Bictash, E Yvonne Jones, Paul V Fish
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.