1365060-89-4Relevant academic research and scientific papers
Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors
Atkinson, Benjamin N.,Bayle, Elliott D.,Bictash, Magda,Fish, Paul V.,Frew, Sarah,Jeganathan, Fiona,Jones, E. Yvonne,Mahy, William,Monaghan, Amy,Papageorgiou, George,Sipthorp, James,Steadman, David,Svensson, Fredrik,Zhao, Yuguang
, (2020)
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.
Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase
Tarver, James E.,Pabba, Praveen K.,Barbosa, Joseph,Han, Qiang,Gardyan, Michael W.,Brommage, Robert,Thompson, Andrea Y.,Schmidt, James M.,Wilson, Alan G.E.,He, Wei,Lombardo, Victoria K.,Carson, Kenneth G.
, p. 1525 - 1528 (2016/07/27)
A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.
INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE
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, (2012/03/27)
Compounds are disclosed for the treatment, management and prevention of diseases and disorders affecting the bone. Particular compounds are potent inhibitors of Notum Pectinacetylesterase, and are of the formula: wherein E, G, Y, Z, R1, R2, and R3 are defined herein.
