Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates

James Edward Dunford, Keith Thompson, Fraser Coxon, S. P. Luckman, F. M. Hahn, C. D. Poulter, F. H. Ebetino, Michael John Rogers

Research output: Contribution to journalArticle

719 Citations (Scopus)

Abstract

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 greater than or equal to1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximate 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 similar to 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.

Original languageEnglish
Pages (from-to)235-242
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume296
Issue number2
Publication statusPublished - Feb 2001

Keywords

  • heterocycle-containing bisphosphonates
  • in-vitro
  • mevalonate pathway
  • isoprenoid biosynthesis
  • pyrophosphate synthase
  • protein prenylation
  • squalene synthase
  • apoptosis
  • osteoclasts
  • activation

Cite this

Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. / Dunford, James Edward; Thompson, Keith; Coxon, Fraser; Luckman, S. P.; Hahn, F. M.; Poulter, C. D.; Ebetino, F. H.; Rogers, Michael John.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 296, No. 2, 02.2001, p. 235-242.

Research output: Contribution to journalArticle

Dunford, James Edward ; Thompson, Keith ; Coxon, Fraser ; Luckman, S. P. ; Hahn, F. M. ; Poulter, C. D. ; Ebetino, F. H. ; Rogers, Michael John. / Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 296, No. 2. pp. 235-242.
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AU - Dunford, James Edward

AU - Thompson, Keith

AU - Coxon, Fraser

AU - Luckman, S. P.

AU - Hahn, F. M.

AU - Poulter, C. D.

AU - Ebetino, F. H.

AU - Rogers, Michael John

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N2 - 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 greater than or equal to1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximate 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 similar to 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.

AB - 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 greater than or equal to1 nM zoledronic acid or minodronate, the order of potency (zoledronic acid approximate 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 similar to 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.

KW - heterocycle-containing bisphosphonates

KW - in-vitro

KW - mevalonate pathway

KW - isoprenoid biosynthesis

KW - pyrophosphate synthase

KW - protein prenylation

KW - squalene synthase

KW - apoptosis

KW - osteoclasts

KW - activation

M3 - Article

VL - 296

SP - 235

EP - 242

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

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