A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase

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Abstract
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. 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. 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. These results from the experiments seem to indicate that osteoclast V‐ATPase may be different from lysosomal V‐ATPase in respect of their structure. 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. British Journal of Pharmacology (2004) 142, 558–566. doi:10.1038/sj.bjp.0705812

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