Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.
Acetylesterase
/ antagonists & inhibitors
Amides
/ chemistry
Animals
Binding Sites
Cell Membrane Permeability
/ drug effects
Crystallography, X-Ray
Dogs
Half-Life
Inhibitory Concentration 50
Madin Darby Canine Kidney Cells
Male
Mice
Mice, Inbred C57BL
Microsomes
/ metabolism
Molecular Dynamics Simulation
Protein Structure, Tertiary
Pyrimidines
/ chemistry
Structure-Activity Relationship
Wnt Signaling Pathway
/ drug effects
CNS penetration
Furano[2,3-d]pyrimidines
Notum inhibitor
SBDD
Wnt signaling
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 02 2020
01 02 2020
Historique:
received:
05
09
2019
revised:
09
10
2019
accepted:
10
10
2019
pubmed:
22
12
2019
medline:
29
1
2021
entrez:
22
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31862412
pii: S0960-894X(19)30714-0
doi: 10.1016/j.bmcl.2019.126751
pmc: PMC6961116
pii:
doi:
Substances chimiques
Amides
0
Pyrimidines
0
Acetylesterase
EC 3.1.1.6
pyrimidine
K8CXK5Q32L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
126751Subventions
Organisme : Cancer Research UK
ID : FC001002
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001002
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001002
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C375/A17721
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
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