Uses
A highly potent bisphosphonate and activator of PKC.
Uses
Zoledronic acid monohydrate is an anti-resorptive agent for cancer bone metasis, also used on studies in the environmental risk asseessment of drugs from view of excretion form to environment.
Brand name
Zometa (Novartis).
General Description
Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards
Biological Activity
Zoledronic acid (Zoledronate, CGP-4244) monohydrate is the monohydrate of Zoledronic acid (Zoledronic acid), a potent osteoclast inhibitor that inhibits small GTP-binding proteins by inhibiting enzymes of the mevalonate pathway Such as the prenylation of Ras and Rho to induce osteoclast apoptosis.
Biochem/physiol Actions
Zoledronic acid (zoledronate) is a bisphosphonate bone resorption inhibitor, an inhibitor of farnesyl diphosphate (FPP) synthase which results in downstream inhibition of osteoclast activity and reduced bone resorption and turnover. It has been used to treat postmenopausal osteoporosis, Paget′s disease, hypercalcemia, and along with cancer chemotherapy to treat bone damage caused by cancer that has spread to the bones.
Synthesis
The general procedure for the synthesis of 1-hydroxy-2-(1-imidazolyl)ethane-1,1-diphosphonic acid hydrate from (1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diphosphonic acid is as follows:
Example 3: Preparation of zoledronic acid monohydrate
The pristine moist zoledronic acid (equivalent to 90.3 g of crude product) obtained according to Example 1 was suspended in 3050 ml of water. The suspension was heated to reflux under stirring conditions. Subsequently, EPO water was added to bring the total volume to 3750 ml until complete dissolution. The heating was stopped and stirring was continued to allow the solution to cool slowly to room temperature. When the internal temperature dropped to about 70-80°C, it was further cooled to 2-5°C and maintained at this temperature for 1 hour. The precipitate was filtered and washed with ice water. The resulting precipitate was dried in an airflow oven. Finally, 169.3 g (89% yield) of colorless crystals were obtained at 5°C to 60°C. The loss of water of crystallization was measured to be 6.8% by thermogravimetric analysis (TGA), confirming the monohydrate. The X-ray powder diffraction (XRPD) pattern of the substance showed characteristic peaks at 2θ values of 12.1°, 12.8°, 15.7°, and 18.9° ± 0.2°, which is consistent with the diffraction data of the known crystalline type I (US 2005/0054616). Figure 1A illustrates its XRPD pattern, while Figure IV shows the arrangement structure of the atoms in the crystal cell.
in vitro
Zoledronic Acid monohydrate (0.1-1 μM; 48 hours) increases receptor activator of nuclear factor kB ligand (RANKL) and sclerostin mRNA expressions in osteocyte-like MLO-Y4 cells.Zoledronic Acid monohydrate increases the expression of osteoclastogenesis supporting factor from MLO-Y4 cells.Zoledronic Acid monohydrate enhances the RANKL expression via IL-6/ JAK2/STAT3 pathway in MLO-Y4 cells.Zoledronic Acid monohydrate inhibits osteoclast differentiation and function through the regulation of NF-κB and JNK signalling pathways.Zoledronic Acid monohydrate (10-100 μM; 1-7 days) markedly reduces the viability of MC3T3-E1 cells.Zoledronic Acid monohydrate (10-100 μM; 1-7 days) induces apoptosis in MC3T3-E1 cells.Zoledronic Acid monohydrate (10-100 μM; 4 days) inhibits cell viability due to the induction of apoptosis.Zoledronic Acid monohydrate exerts inhibitory effects on the differentiation and maturation of MC3T3-E1 cells at concentrations <1 μM.
in vivo
Zoledronic Acid monohydrate (0.05 mg/kg; i.p.; weekly; for 3 weeks) increases bone mineral density and content.Zoledronic Acid monohydrate (0.5-1 mg/kg; i.p.; weekly; for 3 weeks) inhibits both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties.
References
[1] Patent: WO2007/16982, 2007, A1. Location in patent: Page/Page column 7-8
[2] Patent: EP1925621, 2008, A1. Location in patent: Page/Page column 14
