title: Inhibition of bone resorption by H+/K(+)-ATPase inhibitors.
abstract: We have found that 3-(3-(ethoxycarbonyl)propionyl)-8-methoxy-4-((2- methylphenyl)amino)quinoline (1, CP-113,411), a reversible inhibitor of gastric H+/K(+)-ATPase (IC50 10-20 mM), is also a potent inhibitor of bone resorption by osteoclasts in a bone slice assay at concentrations as low as 10(-7) M, with an IC50 of 2 mM. By contrast, the structurally related H+/K(+)-ATPase inhibitor 2 (3-(ethoxycarbonyl)-8-methoxy-4-((2-methylphenyl)amino)quinoline) disclosed by Robins is slightly more potent as an inhibitor of the gastric enzyme (IC50 3-10 microM in our hands) but less efficacious than 1 as an inhibitor of osteoclasts in the bone slice assay at the lower concentrations (no effect at < or = 10(-6) M, IC50 4 mM). These findings suggest that osteoclasts contain an H+/K(+)-ATPase-like enzyme which differs from the gastric one.
authors.affiliation: Pfizer Central Research, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: R
authors.initials: R
authors.lastname: Sarges
authors.forename: A
authors.initials: A
authors.lastname: Gallagher
authors.forename: T J
authors.initials: TJ
authors.lastname: Chambers
authors.forename: L A
authors.initials: LA
authors.lastname: Yeh
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000201:enzymology / Q000517:prevention & control*; D005753:Gastric Mucosa / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D054328:Proton Pump Inhibitors; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine
chemical_list: D000634:Aminoquinolines; D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D013386:Succinates; C069704:3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline; C083399:3-(3-(ethoxycarbonyl)propionyl)-8-methoxy-4-((2-methylphenyl)amino)quinoline; D017506:H(+)-K(+)-Exchanging ATPase