title: Hit to lead studies on (hetero)arylpyrimidines--agonists of the canonical Wnt-beta-catenin cellular messaging system.
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.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, United States. gilbera@wyeth.com
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Nippa
authors.initials: N
authors.lastname: Alon
authors.forename: Bheem M
authors.initials: BM
authors.lastname: Bhat
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Bex
authors.forename: Michael
authors.initials: M
authors.lastname: Cain
authors.forename: Valerie
authors.initials: V
authors.lastname: Coleburn
authors.forename: Virginia
authors.initials: V
authors.lastname: Gironda
authors.forename: Paula
authors.initials: P
authors.lastname: Green
authors.forename: Diane B
authors.initials: DB
authors.lastname: Hauze
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Kharode
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Matthew
authors.initials: M
authors.lastname: Kirisits
authors.forename: Ho-Sun
authors.initials: HS
authors.lastname: Lam
authors.forename: Yao-Bin
authors.initials: YB
authors.lastname: Liu
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lombardi
authors.forename: Jeanne
authors.initials: J
authors.lastname: Matteo
authors.forename: Richard
authors.initials: R
authors.lastname: Murrills
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
authors.forename: Sally
authors.initials: S
authors.lastname: Selim
authors.forename: Michael
authors.initials: M
authors.lastname: Sharp
authors.forename: Raymond
authors.initials: R
authors.lastname: Unwalla
authors.forename: Usha
authors.initials: U
authors.lastname: Varadarajan
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zhao
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yaworsky
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000378:metabolism; D051153:Wnt Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000819:agonists / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3