Abstract
A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Bone Development / drug effects
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Cell Line, Tumor
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / pharmacology
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Recombinant Fusion Proteins / agonists
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Skull / metabolism
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Wnt Proteins / agonists
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt3 Protein
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Wnt3A Protein
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beta Catenin / agonists
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beta Catenin / metabolism*
Substances
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DKK1 protein, human
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Imidazoles
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Intercellular Signaling Peptides and Proteins
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Pyrimidines
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Recombinant Fusion Proteins
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WNT3A protein, human
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Wnt Proteins
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Wnt3 Protein
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Wnt3A Protein
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Wnt3a protein, mouse
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beta Catenin
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Glycogen Synthase Kinase 3