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.
MeSH terms
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Animals
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Catalytic Domain
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Cell Line, Tumor
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / chemistry
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Models, Molecular
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Osteogenesis / drug effects*
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Piperidines / administration & dosage
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Signal Transduction / drug effects
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Wnt Proteins / agonists*
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Wnt Proteins / metabolism
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beta Catenin / agonists*
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beta Catenin / metabolism
Substances
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Piperidines
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Pyrimidines
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WAY-262611
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Wnt Proteins
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beta Catenin
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3