Efficacy, Mechanism, and Structure–Activity Relationship of 6‑Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis

Most patients with senile osteoporosis (SOP) are severely
deficient
in bone mass, and treatments using bone resorption inhibitors, such
as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting
drugs are required to improve the treatment for this disease. Previously,
we demonstrated that a compound with a benzofuran-like structure promoted
bone formation by upregulating BMP-2, and it exhibited a therapeutic
effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and
ovariectomized rats. In this study, aged C57 and SAMP-6 mice models
were used to investigate the therapeutic and preventive effects of
compound 125 on SOP. scRNA-seq analysis showed that BMP-2
upregulation is the mechanism through which 125 accelerates
bone turnover and increases the proportion of osteoblasts. We evaluated
the structure–activity relationship of the candidate drugs
and found that the derivative I-9 showed significantly
higher efficacy than 125 and teriparatide in the zebrafish
osteoporosis model. This study provides a foundation for the development
of SOP drugs.