title: 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity.
abstract: The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.
authors.affiliation: Department of Chemistry, SmithKline Beecham S.p.A., Via Zambeletti, 20021 Baranzate, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: G
authors.initials: G
authors.lastname: Nadler
authors.forename: E
authors.initials: E
authors.lastname: Consolandi
authors.forename: C
authors.initials: C
authors.lastname: Parini
authors.forename: M
authors.initials: M
authors.lastname: Morvan
authors.forename: M N
authors.initials: MN
authors.lastname: Legave
authors.forename: P
authors.initials: P
authors.lastname: Belfiore
authors.forename: A
authors.initials: A
authors.lastname: Zocchetti
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: I
authors.initials: I
authors.lastname: James
authors.forename: P
authors.initials: P
authors.lastname: Nambi
authors.forename: M
authors.initials: M
authors.lastname: Gowen
authors.forename: C
authors.initials: C
authors.lastname: Farina
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D002462:Cell Membrane; D002645:Chickens; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007672:Kidney Cortex / Q000201:enzymology; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014617:Vacuoles / Q000187:drug effects* / Q000201:enzymology
chemical_list: C112098:5-(5,6-dichloro-2-indolyl)-2--methoxy-N-(3-(4-(2-pyrimidinyl)piperazin-1-yl)propyl)-2,4-pentadienamide; C112097:5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(8-methyl-8-azabicyclo(3.2.2)oct-3-yl)-2,4-pentadienamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D007211:Indoles; D011743:Pyrimidines; D006180:Proton-Translocating ATPases