Efficacy,Mechanism,and Structure-Activity Relationship Of 6-Methoxy Benzofuran Derivatives As A Useful Tool For Senile Osteoporosis

In recent years,the global aging process has accelerated,and the incidence of senile osteoporosis(SOP)is increasing year by year,seriously affecting the quality of life and life span of the elderly.And causing huge medical expenses and social burden to the society when fractures occur,making it an important public health problem.In China,most SOP patients seek medical attention late and have severe bone loss at the beginning of treatment.Bisphosphonates are currently the most commonly used drug for treating SOP,which works by inhibiting bone resorption.Although they can prevent further bone loss,they cannot reverse the lost bone mass.Meanwhile,for low conversion osteoporosis such as SOP,the bone resorption level is no longer high,which limits the effectiveness of bisphosphate drugs.The bone formation promoting drugs used in clinical practice are peptides and monoclonal antibodies,which are currently only used for fracture recovery in patients with fractures and short-term treatment in patients with extremely low bone mass.Due to adverse reactions,the treatment cycle is strictly limited to 24 months.Therefore,it is crucial to develop small molecule drugs that promote bone formation and improve the clinical treatment effect of SOP.Bone morphogenetic protein 2(BMP-2)is an effective bone inducing cytokine,whose main biological function is to induce the differentiation of undifferentiated bone marrow mesenchymal stem cells into cartilage and new bone.Previously,our team demonstrated that a class of benzofuran like structures promote bone formation by upregulating BMP-2,demonstrating their efficacy and safety in SAMP-6 mice,glucocorticoid induced osteoporosis rats,and ovariectomized rats.The study of structure-activity relationship shows that the parent nucleus of 6-methoxybenzofuran is the optimal parent nucleus,and the strategy of enhancing drug efficacy by improving water solubility and metabolic stability is effective.In this paper,the therapeutic and preventive effects of representative compound 125 on SOP were first studied using aging C57 and SAMP-6 mouse models,and its clinical application value was clarified.Subsequently,scRNA seq analysis was used to determine the mechanism by which 125 accelerates bone turnover and increases the proportion of osteoblasts through upregulation of BMP-2.Finally,we designed and synthesized 28 new derivatives that have not been reported in the literature,evaluated SAR on a zebrafish osteoporosis model,and clarified the effects of different terminal groups and ligands on activity,improving the SAR of these compounds.In the study of a multi concentration zebrafish osteoporosis pharmacodynamic model,the efficacy of derivative Ⅰ-9 was significantly better than that of 125 and the positive control drug teriparatide.The efficacy of Ⅰ-9 was evaluated through in vivo and in vitro CT and bone slice systems in elderly C57 mice,and preliminary studies on its medicinal properties showed the possibility of long-term oral administration.Ⅰ-9 can continue to be studied as a candidate for small molecule bone formation promoting drugs in the future,and can also serve as a chemical biology tool for in depth research on bone formation promoting mechanisms.This study has promoted the development of SOP drugs.