title: 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.affiliation: Department of Biological Science, Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Japan. kazuaki_niikura@po.fujisawa.co.jp
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Niikura
authors.forename: Mikiko
authors.initials: M
authors.lastname: Takano
authors.forename: Masae
authors.initials: M
authors.lastname: Sawada
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D001862:Bone Resorption / Q000201:enzymology / Q000517:prevention & control*; D002645:Chickens; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012886:Skull / Q000187:drug effects / Q000201:enzymology; D013045:Species Specificity; D013977:Tibia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D001572:Benzofurans; D004791:Enzyme Inhibitors; C495452:FR 167356; D025262:Vacuolar Proton-Translocating ATPases