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

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

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

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2010-01, 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
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Sprache:eng
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Zusammenfassung:A series of (hetero)arylpyrimidines agonists of the Wnt-b-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-3b inhibition indicating that the Wnt-b-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 b-catenin formation in bone.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2009.10.093