Novel bone antiresorptive agents that selectively inhibit the osteoclast V-H+-ATPase
2001; Elsevier BV; Volume: 56; Issue: 1-2 Linguagem: Inglês
10.1016/s0014-827x(01)01013-8
ISSN1879-0569
AutoresCarlo Farina, Stefania Gagliardi, Guy Nadler, Marcel Morvan, Carlo Parini, Pietro Belfiore, L. Visentin, Maxine Gowen,
Tópico(s)Mitochondrial Function and Pathology
ResumoThe 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.
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