title: Novel bone antiresorptive agents that selectively inhibit the osteoclast V-H+-ATPase.
abstract: The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is a potential molecular target for the discovery of novel bone antiresorptive agents useful for the treatment of osteoporosis. In order to design novel compounds able to selectively inhibit the osteoclast V-ATPase we firstly identified the minimal structural requirements of bafilomycin A1, a macrolide antibiotic which potently inhibits all V-ATPases. This information allowed the design of 2-(indole)pentadienamide derivatives whose optimization led to a novel class of potent inhibitors that demonstrated a high degree of selectivity for the osteoclast V-ATPase. The most interesting derivative, SB-242784, was able to inhibit bone resorption by human osteoclasts in vitro and to completely prevent ovariectomy-induced bone loss in rats when administered orally at 10 mg kg(-1) day(-1). Structure activity relationships of this class of compounds were investigated further by replacing the 2,4-pentadienoyl chain with suitable spacers able to maintain the correct orientation and distance between the indole ring and the amide moiety.
authors.affiliation: SmithKline Beecham SpA, Baranzate, Milan, Italy. carlo_farina@gsk.com
authors.forename: C
authors.initials: C
authors.lastname: Farina
authors.forename: S
authors.initials: S
authors.lastname: Gagliardi
authors.forename: G
authors.initials: G
authors.lastname: Nadler
authors.forename: M
authors.initials: M
authors.lastname: Morvan
authors.forename: C
authors.initials: C
authors.lastname: Parini
authors.forename: P
authors.initials: P
authors.lastname: Belfiore
authors.forename: L
authors.initials: L
authors.lastname: Visentin
authors.forename: M
authors.initials: M
authors.lastname: Gowen
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology; D010024:Osteoporosis / Q000517:prevention & control; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D004791:Enzyme Inhibitors; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases