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

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.

• Authors: Kazuaki Niikura, Mikiko Takano, Masae Sawada
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 142 Issue 3 Pg. 558-66 (Jun 2004) ISSN: 0007-1188 [Print] England
• PMID: 15148249 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Benzofurans
• Enzyme Inhibitors
• FR 167356
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Benzamides (pharmacology)
• Benzofurans (pharmacology)
• Bone Resorption (enzymology, prevention & control)
• Chickens
• Enzyme Inhibitors (pharmacology)
• Female
• Liver (cytology, drug effects, enzymology)
• Lysosomes (drug effects, enzymology)
• Male
• Mice
• Mice, Inbred ICR
• Osteoclasts (drug effects, enzymology)
• Pregnancy
• Rabbits
• Rats
• Rats, Wistar
• Skull (drug effects, enzymology)
• Species Specificity
• Tibia (cytology, drug effects, enzymology)
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors)