1. (1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Wingless β-Catenin Agonist That Increases Bone Formation Rate
- Author
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Diane B. Hauze, Michael C. Sharp, Bheem M. Bhat, Paula Green, Colleen Milligan, Daniel M. Green, Jennifer Pirrello, Peter V.N. Bodine, Ronald L. Magolda, Adam M. Gilbert, Matthew D. Vera, Yogendra P. Kharode, Valerie E. Coleburn, Luciana De Araujo Felix, Mattew G. Bursavich, Nipa Alon, Jeanne J. Matteo, Jay Wrobel, Frederick J. Bex, Jeffrey C. Pelletier, Susan Lockhead, Joseph T. Lundquist, Richard J. Murrills, Ray Unwalla, Paul J. Yaworsky, Sally Selim, John F. Mehlmann, and Ho-Sun Lam
- Subjects
Models, Molecular ,Agonist ,medicine.drug_class ,Pharmacology ,Glycogen Synthase Kinase 3 ,Mice ,Piperidines ,Pharmacokinetics ,Osteogenesis ,Oral administration ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,beta Catenin ,Glycogen Synthase Kinase 3 beta ,Chemistry ,Wnt signaling pathway ,Small molecule ,In vitro ,Rats ,Wnt Proteins ,Pyrimidines ,Biochemistry ,Catenin ,Ovariectomized rat ,Molecular Medicine ,Signal Transduction - Abstract
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.
- Published
- 2009
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