Novel bone antiresorptive agents that selectively inhibit the osteoclast V-H+-ATPase.
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.
Farina
C
C
SmithKline Beecham SpA, Baranzate, Milan, Italy. carlo_farina@gsk.com
Gagliardi
S
S
Nadler
G
G
Morvan
M
M
Parini
C
C
Belfiore
P
P
Visentin
L
L
Gowen
M
M
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
D004791:Enzyme Inhibitors; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases