(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: a wingless beta-catenin agonist that increases bone formation rate.
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.
Pelletier
Jeffrey C
JC
Chemical Sciences, Drug Safety & Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Pelletj@wyeth.com
Lundquist
Joseph T
JT
Gilbert
Adam M
AM
Alon
Nipa
N
Bex
Frederick J
FJ
Bhat
Bheem M
BM
Bursavich
Mattew G
MG
Coleburn
Valerie E
VE
Felix
Luciana A
LA
Green
Daniel M
DM
Green
Paula
P
Hauze
Diane B
DB
Kharode
Yogendra P
YP
Lam
Ho-Sun
HS
Lockhead
Susan R
SR
Magolda
Ronald L
RL
Matteo
Jeanne J
JJ
Mehlmann
John F
JF
Milligan
Colleen
C
Murrills
Richard J
RJ
Pirrello
Jennifer
J
Selim
Sally
S
Sharp
Michael C
MC
Unwalla
Ray J
RJ
Vera
Matthew D
MD
Wrobel
Jay E
JE
Yaworsky
Paul
P
Bodine
Peter V N
PV
D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010012:Osteogenesis / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000819:agonists* / Q000378:metabolism; D051176:beta Catenin / Q000819:agonists* / Q000378:metabolism; D009281:Naphthalenes
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D010880:Piperidines; D011743:Pyrimidines; D051153:Wnt Proteins; D051176:beta Catenin; C545683:WAY-262611; D009281:Naphthalenes