(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Wingless β-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 β-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-11, Vol.52 (22), p.6962-6965
Main Authors: Pelletier, Jeffrey C, Lundquist, Joseph T, Gilbert, Adam M, Alon, Nipa, Bex, Frederick J, Bhat, Bheem M, Bursavich, Mattew G, Coleburn, Valerie E, Felix, Luciana A, Green, Daniel M, Green, Paula, Hauze, Diane B, Kharode, Yogendra P, Lam, Ho-Sun, Lockhead, Susan R, Magolda, Ronald L, Matteo, Jeanne J, Mehlmann, John F, Milligan, Colleen, Murrills, Richard J, Pirrello, Jennifer, Selim, Sally, Sharp, Michael C, Unwalla, Ray J, Vera, Matthew D, Wrobel, Jay E, Yaworsky, Paul, Bodine, Peter V. N
Format: Article
Language:English
Subjects:
Animals
beta Catenin - agonists
beta Catenin - metabolism
Catalytic Domain
Cell Line, Tumor
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Glycogen Synthase Kinase 3 - chemistry
Glycogen Synthase Kinase 3 beta
Humans
Mice
Models, Molecular
Osteogenesis - drug effects
Piperidines - administration & dosage
Piperidines - pharmacokinetics
Piperidines - pharmacology
Pyrimidines - administration & dosage
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Rats
Signal Transduction - drug effects
Wnt Proteins - agonists
Wnt Proteins - metabolism
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Summary: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 β-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9014197