Pharmacological characterization of AS2690168, a novel small molecule RANKL signal transduction inhibitor

Pathological osteolysis is associated with excessive bone resorption by activated osteoclasts. Given that receptor activator of NF-kB and its ligand (RANKL) are key players in the differentiation and activation of osteoclasts, the RANKL/RANK signaling pathway is considered a promising target for the development of effective osteoclastogenesis inhibitors. We previously found that the orally available compound, AS2690168, suppresses RANKL-induced osteoclastogenesis of RAW264 cells. In this report, we further characterized the pharmacological profiles of AS2690168 in vitro and in vivo. AS2690168 suppressed soluble RANKL (sRANKL)-induced NFATc1 mRNA expression in RAW264 cells at 0.3 and 3.0 μM. It also suppressed calcium release from parathyroid hormone-stimulated mouse calvaria with an IC₅₀ value of 0.46 μM. Oral administration of AS2690168 completely suppressed the decrease in femoral bone mineral content in an sRANKL-induced osteopenic mice model at 3.0 mg/kg. It also significantly suppressed the decrease in femoral bone mineral density and increase in serum tartrate-resistant acid phosphatase-5b levels in ovariectomized rats at doses of 0.3, 1 and 3 mg/kg. Finally, AS260168 suppressed the increase in urine deoxypyridinoline in a rat prednisolone-induced osteoporosis model at 10 mg/kg. These results suggest that AS2690168 is a promising treatment for bone disorders with excessive bone resorption.

Inhibitor; Osteoporosis; RANKL.