論文 - 詳細
| RRC ID | 6471 |
|---|---|
| 著者 | Niikura K, Takano M, Sawada M. |
| タイトル | A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase. |
| ジャーナル | Br J Pharmacol |
| Abstract |
1 Vacuolar ATPase (V-ATPase) has been proposed as a drug target in lytic bone diseases. Studies of bafilomycin derivatives suggest that the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is selective inhibition of osteoclast V-ATPase. Previous efforts to develop therapeutic inhibitors of osteoclast V-ATPase have been frustrated by a lack of synthetically tractable and biologically selective leads. Therefore, we tried to find novel potent and specific V-ATPase inhibitors, which have new structural features and inhibition selectivity, from random screening using osteoclast microsomes. Finally, a novel V-ATPase inhibitor, FR167356, was obtained through chemical modification of a parental hit compound. 2 FR167356 inhibited not only H+ transport activity of osteoclast V-ATPase but also H+ extrusion from cytoplasm of osteoclasts, which depends on the V-ATPase activity. As expected, FR167356 remarkably inhibited bone resorption in vitro. 3 FR167356 also showed inhibitory effects on other V-ATPases, renal brush border V-ATPase, macrophage microsome V-ATPase and lysosomal V-ATPase. However, FR167356 was approximately seven-fold less potent in inhibiting lysosomal V-ATPase compared to osteoclast V-ATPase. Moreover, LDL metabolism in cells, which depends on acidification of lysosome, was blocked merely at higher concentration than bone resorption, suggesting that FR167356 inhibits V-ATPase of osteoclast ruffled border membrane still more selectively than lysosome at the cellular level. 4 These results from the experiments seem to indicate that osteoclast V-ATPase may be different from lysosomal V-ATPase in respect of their structure. 5 FR167356 had a novel chemical structural feature as well as inhibitory characteristics distinctly different from any previously known V-ATPase inhibitor family. Therefore, FR167356 is thought to be a useful tool for estimating the essential characteristics of V-ATPase inhibitors for drug development. |
| 巻・号 | 142(3) |
| ページ | 558-66 |
| 公開日 | 2004-6-1 |
| DOI | 10.1038/sj.bjp.0705812 |
| PII | 0705812 |
| PMID | 15148249 |
| PMC | PMC1574973 |
| MeSH | Animals Benzamides / pharmacology* Benzofurans / pharmacology* Bone Resorption / enzymology Bone Resorption / prevention & control* Chickens Enzyme Inhibitors / pharmacology* Female Liver / cytology Liver / drug effects Liver / enzymology Lysosomes / drug effects* Lysosomes / enzymology Male Mice Mice, Inbred ICR Osteoclasts / drug effects* Osteoclasts / enzymology Pregnancy Rabbits Rats Rats, Wistar Skull / drug effects Skull / enzymology Species Specificity Tibia / cytology Tibia / drug effects Tibia / enzymology Vacuolar Proton-Translocating ATPases / antagonists & inhibitors* |
| 引用数 | 10 |
| WOS 分野 | NUTRITION & DIETETICS |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 10 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |