Hit to lead studies on (hetero)arylpyrimidines—Agonists of the canonical Wnt-β-catenin cellular messaging system

A series of (hetero)arylpyrimidines agonists of the Wnt-β-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-3β inhibition indicating that the Wnt-β-caten...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010, Vol.20 (1), p.366-370
Hauptverfasser:	Gilbert, Adam M., Bursavich, Matthew G., Alon, Nippa, Bhat, Bheem M., Bex, Frederick J., Cain, Michael, Coleburn, Valerie, Gironda, Virginia, Green, Paula, Hauze, Diane B., Kharode, Yogendra, Krishnamurthy, Girija, Kirisits, Matthew, Lam, Ho-Sun, Liu, Yao-Bin, Lombardi, Sabrina, Matteo, Jeanne, Murrills, Richard, Robinson, John A., Selim, Sally, Sharp, Michael, Unwalla, Raymond, Varadarajan, Usha, Zhao, Weiguang, Yaworsky, Paul J.
Format:	Artikel
Sprache:	eng
Schlagworte:	(Hetero)arylpyrimidines Animals beta Catenin - agonists beta Catenin - metabolism Biological and medical sciences Bone Development - drug effects Bones, joints and connective tissue. Antiinflammatory agents Calvaria Cell Line, Tumor Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Medical sciences Mice Mice, Inbred C57BL Osteoporosis Pharmacology. Drug treatments Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Recombinant Fusion Proteins - agonists Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Signal Transduction Skull - metabolism Wnt Proteins - agonists Wnt Proteins - genetics Wnt Proteins - metabolism Wnt-β-catenin agonist Wnt3 Protein Wnt3A Protein
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Beschreibung
Zusammenfassung:	A series of (hetero)arylpyrimidines agonists of the Wnt-β-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-3β inhibition indicating that the Wnt-β-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 β-catenin formation in bone.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.10.093