Osteoporosis is a bone disease characterized by low bone mass and structural degradation of bone tissue. Currently used osteoporosis treatments such as estrogens, selective estrogen modulators, calcitonin and bisphosphonates are mainly beneficial for reducing bone resorption; there are also some therapeutic drugs such as fluoride and Parathyroid hormone can increase bone formation.
Anti-bone resorption therapy is very effective in the treatment of osteoporosis, even though it usually does not induce the formation of new bone. To date, bisphosphonates are still the most widely used anti-resorptive drugs, all of which are synthetic analogues of the endogenous mineral deposit inhibitor pyrophosphate, which inhibits bone resorption and increases bone mineral density ( BMD) can effectively treat osteoporosis, Paget's disease and tumor-associated bone disease, but its mechanism of action is still unclear. Studies have shown that bisphosphonates can be endocytosed specifically by osteoclasts, thereby inhibiting their activity and inducing apoptosis; bisphosphonates such as clodronate and etidronate are structurally Similar to pyrophosphate, it can be metabolized to cytotoxic analogues of ATP in vivo to inhibit osteoclast activity; nitrogen-containing bisphosphonates such as pamidronate, ibandronate, alendronate And zoledronate induce osteoclast apoptosis by inhibiting key enzymes in the mevalonate pathway [as in the formation of the farnesyl diphosphate (FPP) process] and inhibit small molecule GTP-binding proteins (such as Ras and Rhodylation of minodronic acid synthesized by Yamanouchi(minodronicacid, YM2529, Ono25920, YH2529) is the third
The aza-heteroaryl bisphosphonate derivative has an anti-bone resorption activity 100-1000 times higher than that of pamidronate, and can antagonize the osteolysis caused by myeloma and tumor.
Pharmacological effects: A pharmacological study compared the inhibition of the mevalonate pathway by several nitrogen-containing bisphosphonates. The results showed that FPP synthase is the main pharmacological target of minodronic acid and other bisphosphonates. Point; concentration is 1nmol·L-1
Or the above minodronic acid (the main raw material is Ethyl trans-4-oxo-2-butenoate) can effectively inhibit recombinant human FPP synthase (IC50=01003μmol·L-1) in a similar manner to zoledronic acid in vitro. ). Arranged in order of activity of such bisphosphonates, followed by zoledronic acid, minodronic acid, risedronate, ibandronic acid, incadinate, alendronate, pamidron Acid salt. The activity of these bisphosphonates is closely related to their ability to inhibit prenylation in cell-free extracts (rabbit reticulocyte lysates) and purified osteoclasts and to inhibit bone resorption in rats.