二乙基 4-((6R,8S)-8-甲基-9-氧亚基-5,6,8,9-四氢噻庚英并[4,5:4,5]苯并[1,2-D][1,3]二噁戊环-6-碳杂草酰氨基)苯甲基膦酸基酯

TAK-778 is a derivative of ipriflavone and has been shown to induce bone growth in in vitro and in vivo models. Continuous treatment with TAK-778 (10 μM) for 1 to 21 days results in an increase in the area of mineralized nodules. TAK-778 at concentrations of 1 μM and higher significantly stimulates the activity of cellular Alkaline phosphatase (ALP). TAK-778 increases slightly but significantly the DNA content of the cells at the confluence stage. Treatment with TAK-778 also results in dose-dependent increases in the amount of soluble collagen and osteocalcin secreted into culture medium from days 5 to 7. TAK-778 enhances the secretion of both TGF-β and IGF-I at every time point during the 21 days of culture. Treatment of the cells with TAK-778 does not induce ALP activity, but does result in a dose-dependent increase in the saturated cell density. TAK-778 at a concentration of 10 μM significantly reduces the saturated cell density.

Treatment with a single local application of TAK-778/PLGA-MC (0.2 to 5 mg/site) results in a dose-dependent increase in the radio-opaque area formed in the defect. Histological studies show the defect area is occupied by a bony bridge and the newly-formed radio-opaque area corresponds to a calcified bone containing bone marrow cavities surrounded by thick osteoid seams with cuboidal osteoblasts. There is no significant difference in either of the indices between placebo- or TAK-778/PLGA-MC-treated skulls. Two months after the operation, the TAK-778/PLGA-MC pellets induce radiological osseous union across the defects. Oral treatment of OVX rats with TAK-778 causes a more pronounced increase in bone mineral density (BMD) of the lumbar vertebrae compare to vehicle controls.