Hit to lead studies on (hetero)arylpyrimidines--agonists of the canonical Wnt-beta-catenin cellular messaging system.
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.
Gilbert
Adam M
AM
Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, United States. gilbera@wyeth.com
Bursavich
Matthew G
MG
Alon
Nippa
N
Bhat
Bheem M
BM
Bex
Frederick J
FJ
Cain
Michael
M
Coleburn
Valerie
V
Gironda
Virginia
V
Green
Paula
P
Hauze
Diane B
DB
Kharode
Yogendra
Y
Krishnamurthy
Girija
G
Kirisits
Matthew
M
Lam
Ho-Sun
HS
Liu
Yao-Bin
YB
Lombardi
Sabrina
S
Matteo
Jeanne
J
Murrills
Richard
R
Robinson
John A
JA
Selim
Sally
S
Sharp
Michael
M
Unwalla
Raymond
R
Varadarajan
Usha
U
Zhao
Weiguang
W
Yaworsky
Paul J
PJ
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*
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