- Pharmacological evaluation of imidazole-derived bisphosphonates on receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation and function
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Bisphosphonates (BPs) have been commonly used in the treatment of osteolytic bone lesions, such as osteoporosis and osteogenesis imperfecta. However, serious side-effects can occur during the therapy. To search for novel potent BPs with lower side-effects, a series of imidazole-containing BPs (zoledronic acid [ZOL]; ZOL derivatives by substitution of the hydrogen at the 2-position on the imidazole ring with a methyl [MIDP], ethyl [EIDP], n-propyl [PIDP], or n-butyl group [BIDP]) were developed and the effects on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation were investigated using the murine macrophage RAW 264.7 cells at the protein, gene, and morphological and functional levels. Influences of these BPs on the cell growth and proliferation of RAW 264.7 were also studied in order to determine cytotoxicity. The results showed that PIDP significantly inhibited the RANKL-induced osteoclast formation in a dose-dependent fashion without inducing cytotoxicity under the concentration of 12.5?μM. It exerted remarkable suppressive effects on the development of actin rings, the bone resorption, and the expressions of osteoclastogenesis-related gene and protein markers. The down-regulation of c-Jun N-terminal kinase (JNK), protein kinase B (Akt), and inhibitor of nuclear factor kappa-B (IκB) phosphorylation in the early signaling event and subsequent inhibition of the expression of c-Fos and nuclear factor of activated T cells (NFATc1) might be involved in these effects. All these results indicated that PIDP might be a promising drug to treat bone-related disorders.
- Lin, Jianguo,Peng, Ying,Liu, Qingzhu,Li, Ke,Lv, Gaochao,Seimbille, Yann,Huang, Gang,Gao, Feng,Qiu, Ling
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p. 121 - 133
(2020/08/10)
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- 2-alkyl substituted imidazolyl diphosphonic acid compound as well as preparation method and application thereof
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The invention belongs to the field of medicinal chemistry, and particularly relates to a 2-alkyl substituted imidazolyl diphosphonic acid compound as well as a preparation method and application thereof. The 2-alkyl substituted imidazolyl diphosphonic acid compound has a larger nontoxic concentration interval for a precursor of an osteoclast, meanwhile, can obviously inhibit the formation of the osteoclast, can furthest destroy an actin ring, and regulates and controls the expression of a relevant gene, inhibits the formation of the osteoclast through decreasing the rise of the mRNA (messenger Ribonucleic Acid) level expression of marker genes, which are related to the formation of the osteoclast, of MMP-9 (Matrix Metallopeptidase-9), Cathepsin K, c-Fos, NFATcl, RANK (Receptor Activator of Nuclear factor Kappa-B) and the like in the osteoclast, inhibits the bone resorption function of the osteoclast through decreasing the expression rises of TRPV5 and integrin beta 3, which are caused by RANKL (Receptor Activator of Nuclear factor Kappa-B Ligand), and can be used as an inhibitor for the osteoclast; the problems that diphosphonate has a low inhibition effect on the osteoclast, is high in toxicity, and further high in side effect in the prior art are solved.
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Paragraph 0079; 0082; 0083
(2017/07/20)
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- THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 216
(2012/02/02)
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