Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships

Beek, Ermond R. van; Löwik, Clemens W.G.M.; Ebetino, Frank H.; Papapoulos, Socrates E.

doi:10.1016/s8756-3282(98)00120-3

Cited by 113 publications

(79 citation statements)

References 12 publications

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“…RIS was considerably more potent than NE10790 at reducing J774 cell viability, whereas NE10485 (which did not inhibit protein prenylation) had no effect on J774 cells. NE10790 was also ϳ100 times less potent than RIS at inhibiting bone resorption by rabbit osteoclasts in vitro, in agreement with another in vitro study using organ cultures of bone (21). However, unlike RIS, NE10790 had little effect on the actin cytoskeleton of osteoclasts.…”

Section: Figsupporting

confidence: 87%

“…NE10790 retains the ability to inhibit bone resorption in vivo, although its antiresorptive potency in rodents is markedly reduced compared with RIS (20). At least part of this loss of potency is due to the fact that NE10790 has reduced affinity for bone, because the loss of one of the phosphonate groups allows binding of only one calcium ion (21). However, it remains unclear whether this compound is also less effective at affecting osteoclast function at the cellular level or indeed whether it inhibits bone resorption by the same molecular mechanism as nitrogen-containing BPs (that is, by inhibition of FPP synthase).…”

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confidence: 99%

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Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Coxon

Helfrich²,

Larijani

et al. 2001

Journal of Biological Chemistry

158

161

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Nitrogen-containing bisphosphonate drugs inhibit bone resorption by inhibiting FPP synthase and thereby preventing the synthesis of isoprenoid lipids required for protein prenylation in bone-resorbing osteoclasts. NE10790 is a phosphonocarboxylate analogue of the potent bisphosphonate risedronate and is a weak antiresorptive agent. Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass ϳ22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298). These 22-26-kDa proteins were shown to be geranylgeranylated by labelling J774 cells with [ 3 H]geranylgeraniol. Furthermore, NE10790 inhibited incorporation of [ 14 C]mevalonic acid into Rab6, but not into H-Ras or Rap1, proteins that are modified by FTase and GGTase I, respectively. These data demonstrate that NE10790 selectively prevents Rab prenylation in intact cells. In accord, NE10790 inhibited the activity of recombinant Rab GGTase in vitro, but did not affect the activity of recombinant FTase or GGTase I. NE10790 therefore appears to be the first specific inhibitor of Rab GGTase to be identified. In contrast to risedronate, NE10790 inhibited bone resorption in vitro without markedly affecting osteoclast number or the F-actin "ring" structure in polarized osteoclasts. However, NE10790 did alter osteoclast morphology, causing the formation of large intracellular vacuoles and protrusion of the basolateral membrane into large, "domed" structures that lacked microvilli. The anti-resorptive activity of NE10790 is thus likely due to disruption of Rabdependent intracellular membrane trafficking in osteoclasts.

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Section: Figsupporting

confidence: 87%

mentioning

confidence: 99%

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Coxon

Helfrich²,

Larijani

et al. 2001

Journal of Biological Chemistry

158

161

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“…BPs are the most widely used and the most effective bone resorption inhibitors currently available for treatment of Paget's disease, tumour-associated bone disease and osteoporosis. All BPs have high affinity for bone mineral as a consequence of their P-C-P backbone structure, which allows chelation of calcium ions (Ebetino et al, 1998). Following release from bone mineral during acidification by osteoclasts, BPs appear to be internalized specifically by osteoclasts, but not other bone cells.…”

Section: Carbohydrates and Their Derivatives As Crystallization Modifmentioning

confidence: 99%

Investigation of Carbohydrates and Their Derivatives as Crystallization Modifiers

Jampílek¹,

Dohnal²

2012

Carbohydrates - Comprehensive Studies on Glycobiology and Glycotechnology

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“…2 Since then, many BPs were synthesized and made commercially available due to their value in the treatment of disorders of bone mineral. 3 These compounds have high affinity for calcium and therefore to target the bone mineral, where they appear to be internalized selectively by bone-reabsorbing osteoclasts and induce their apoptosis. 4 BPs offer several advantages in treating osteoporosis since they are bone-tissue specific, have minimal side less studied in comparison with other heteroaromatic compounds, such as indole or benzimidazole.…”

Section: Introductionmentioning

confidence: 99%

Novel 1-hydroxy-1,1-bisphosphonates derived from indazole: synthesis and characterization

Teixeira¹,

Antunes²,

Curto³

et al. 2009

Arkivoc

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Bisphosphonates (BPs) are an important class of drugs used in the treatment of abnormal calcium metabolism diseases. The first syntheses of bisphosphonates derived from indazole, substituted at the N-1, N-2 and C-3 positions are reported. The 1-hydroxy-1,1-bisphosphonates were synthesized from the corresponding carboxylic acid or acyl chloride compounds, by two different methods. These BPs have a side chain with different lengths ((CH 2 ) n , n = 0-5) between the indazole ring and the bisphosphonate group.

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Binding and antiresorptive properties of heterocycle-containing bisphosphonate analogs: structure-activity relationships

Cited by 113 publications

References 12 publications

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Identification of a Novel Phosphonocarboxylate Inhibitor of Rab Geranylgeranyl Transferase That Specifically Prevents Rab Prenylation in Osteoclasts and Macrophages

Investigation of Carbohydrates and Their Derivatives as Crystallization Modifiers

Novel 1-hydroxy-1,1-bisphosphonates derived from indazole: synthesis and characterization

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