Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates.
By J. Dunford, K. Thompson, F. Coxon, S. P. Luckman, F. M. Hahn, C. Poulter, F. H. Ebetino, M. Rogers. Journal of Pharmacology and Experimental Therapeutics, 2001
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It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonates were found to inhibit osteoclast-mediated bone resorption in vitro by inhibiting farnesyl diphosphate synthase, thereby preventing protein prenylation in osteoclasts. In this study, we examined the potency of a wider range of nitrogen-containing bisphosphonates, including the highly potent, heterocycle-containing zoledronic acid and minodronate (YM-529). We found a clear correlation between the ability to inhibit farnesyl diphosphate synthase in vitro, to inhibit protein prenylation in cell-free extracts and in purified osteoclasts in vitro, and to inhibit bone resorption in vivo. The activity of recombinant human farnesyl diphosphate synthase was inhibited at concentrations > or = 1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximately equal to minodronate > risedronate > ibandronate > incadronate > alendronate > pamidronate) closely matching the order of antiresorptive potency. Furthermore, minor changes to the structure of the R(2) side chain of heterocycle-containing bisphosphonates, giving rise to less potent inhibitors of bone resorption in vivo, also caused a reduction in potency up to approximately 300-fold for inhibition of farnesyl diphosphate synthase in vitro. These data indicate that farnesyl diphosphate synthase is the major pharmacological target of these drugs in vivo, and that small changes to the structure of the R(2) side chain alter antiresorptive potency by affecting the ability to inhibit farnesyl diphosphate synthase.
Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/05383d24754f1f8cb6f4a1c58319bb8ce5c6ca72
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Citations in the corpus
- Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. (2006, background): “These enhancements in antiresorptive potency resulting from differences in the R2 groups appear to be linked to the biochemical activities of these drugs, particularly inhibition of the farnesyl diphosphate synthase enzyme within the mevalonic acid pathway in osteoclasts [19–21].”
- Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy (2008, background): “– The rank order inhibitory potency of N-BPs on FPPS closely matches their rank order of antiresorptive potency in animal models [33].”
- Human T Cell Receptor γδ Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells (2003, background): “This differential likely reflects the greater potency of ZOL in inhibiting FPP synthase (20).”
- Bisphosphonates: the first 40 years. (2011, background): “Many observations point to the importance of the mevalonate pathway for osteoclast function, and validate the notion that N-BPs act by inhibition of this pathway [172–177].”