Modified Quinoxaline‐Fused Oleanolic Acid Derivatives as Inhibitors of Osteoclastogenesis and Potential Agent in Anti‐Osteoporosis

Abstract

AbstractOsteoporosis is one of the most common diseases for aged people, posing a heavy burden to our aging society. Inhibition of osteoclastogenesis is a main strategy to prevent bone loss or bone micro architecture deterioration caused by postmenopausal osteoporosis. In current study, a series of quinoxaline‐fused oleanolic acid (QOA) derivatives were designed and synthesized. Their inhibitory activity on receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclastogenesis was evaluated using a cell‐based tartrate‐resistant acid phosphatase (TRAP) assay. The most potent compound, QOA derivative 5 l, showed an IC50 at 62.4 nM, and cytotoxicity assay of bone marrow‐derived monocyte/macrophage (BMDMs) suggested that the inhibition of 5 l on osteoclast differentiation was not due to its cytotoxicity. More importantly, 5 l attenuated bone loss in the bilateral ovariectomy (OVX) mice model, and preliminary mechanism study indicated that 5 l affected the early stage of osteoclastogenesis. Our data demonstrated that these QOA derivatives might serve as potential leads for the development of new anti‐osteoporosis agents.