Atkinson_2019_Bioorg.Med.Chem.Lett__126751

Reference

Title : Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors - Atkinson_2019_Bioorg.Med.Chem.Lett__126751
Author(s) : Atkinson BN , Steadman D , Mahy W , Zhao Y , Sipthorp J , Bayle ED , Svensson F , Papageorgiou G , Jeganathan F , Frew S , Monaghan A , Bictash M , Jones EY , Fish PV
Ref : Bioorganic & Medicinal Chemistry Lett , :126751 , 2019
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.
ESTHER : Atkinson_2019_Bioorg.Med.Chem.Lett__126751
PubMedSearch : Atkinson_2019_Bioorg.Med.Chem.Lett__126751
PubMedID: 31862412
Gene_locus related to this paper: human-NOTUM

Related information

Gene_locus related to this paper: human-NOTUM

Citations formats

Atkinson BN, Steadman D, Mahy W, Zhao Y, Sipthorp J, Bayle ED, Svensson F, Papageorgiou G, Jeganathan F, Frew S, Monaghan A, Bictash M, Jones EY, Fish PV (2019)
Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors
Bioorganic & Medicinal Chemistry Lett :126751

Atkinson BN, Steadman D, Mahy W, Zhao Y, Sipthorp J, Bayle ED, Svensson F, Papageorgiou G, Jeganathan F, Frew S, Monaghan A, Bictash M, Jones EY, Fish PV (2019)
Bioorganic & Medicinal Chemistry Lett :126751