In vitro activity: WAY-262611 is a novel agonist of the wingless β-Catenin pathway that increases bone formation rate with EC50 of 0.63 uM in TCF-Luciferase assay. WAY-262611 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration. WAY-262611 acts via the Wnt β-catenin pathway and most likely through inhibition of Dkk-1. WAY-262611 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration. WAY-262611 was discovered from a high-throughput screening (HTS) 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).

Kinase Assay: WAY-262611 is a novel agonist of the wingless β-Catenin pathway that increases bone formation rate with EC50 of 0.63 uM in TCF-Luciferase assay. WAY-262611 has the most potent activity in the primary assay, low kinase inhibition potential, and high solubility.

Mice: To confirm activity via the Wnt pathway, the calvariae of wild type (wt) and Dkk-1 knockout (KO) mice are treated with 5 once a day for 7 days (DMSO solution, sc injection). The KO animals are not expected to respond because of the inherent inability to inhibit a missing target protein, while wild type animals with fully expressed Dkk-1 are expected to show a pharmacological response.