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Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Feb 01; Vol. 30 (3), pp. 126751. Date of Electronic Publication: 2019 Oct 28. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Acetylesterase metabolism
Amides metabolism
Amides pharmacology
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
Structure-Activity Relationship
Wnt Signaling Pathway drug effects
Acetylesterase antagonists & inhibitors
Amides chemistry
Pyrimidines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 31862412
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.126751