A Novel Series of Coumarin Derivatives That Exert Osteoblastogenic Effects in Mesenchymal Stem Cells and Osteogenic Effects in Ovariectomized Female Rats

Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. However, orally active small-molecule osteogenic drugs are not clinically available. Natural coumarin derivatives, such as osthole, exert osteoblastogenic effects. In the present study, novel 4,6-substituted coumarin derivatives were synthesized, and their osteoblastogenic effects were assessed in a bone mesenchymal stem cell line (ST2 cell), and structure-activity relationships were discussed. Among the derivatives tested, the osteoblastogenic effects of 2-oxo-4-[4-(tetrahydro-2H-pyran-4-yloxymethyl)phenyl]-2H-chromene-6-carboxamide (11m) and 2-oxo-4-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2H-chromene-6-carboxamide (29v) were potent: EC₂₀₀ for increasing alkaline phosphatase (ALP) activity were 34 and 24 nM, respectively. The maximal plasma concentrations (C_max) of 11m and 29v (10 mg/kg, per os (p.o.)) in female rats were 3637 and 975 nM, respectively, resulting in high C_max/EC₂₀₀ ratios of 105.9 and 40.8, respectively, indicating possible osteoblastogenic effects in vivo. Compound 11m (10 mg/kg, p.o., 8 weeks) was previously reported to increase plasma bone-type ALP activity as well as femoral metaphyseal and diaphyseal cortical bone volumes and mineral contents in micro-computed tomography analyses of ovariectomized female rats (OVX rats). Compound 29v at the same dose also exerted osteoblastogenic and osteogenic effects in OVX rats; however, these effects were weaker than those of 11m. Furthermore, 11m and 29v inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that their osteoblastogenic effects involved the suppression of CDK8. In conclusion, a synthetic 4,6-substituted coumarin structure is a useful scaffold for osteoblastogenic and osteogenic compounds via the inhibition of CDK8, and 11m and 29v have potential as anti-osteoporotic drugs that exert osteogenic effects on cortical bone.