Tmic
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Record Information
Version2.0
Creation Date2009-07-15 20:44:41 UTC
Update Date2014-12-24 20:25:48 UTC
Accession NumberT3D2669
Identification
Common NameZoledronate
ClassSmall Molecule
DescriptionZoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases. An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture. Zoledronate is a single 5 mg infusion for the treatment of Paget's disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.
Compound Type
  • Antihypocalcemic Agent
  • Antiresorptive
  • Bisphosphonate
  • Bone Density Conservation Agent
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene)bisphosphonic acid
(1-Hydroxy-2-imidazol-1-ylethylidene)diphosphonic acid
Aclasta
Reclast
ZOL
Zoledronic acid
Zometa
Zometa Concentrate
Chemical FormulaC5H10N2O7P2
Average Molecular Mass272.090 g/mol
Monoisotopic Mass271.996 g/mol
CAS Registry Number118072-93-8
IUPAC Name[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid
Traditional Namezoledronate
SMILESOC(CN1C=CN=C1)(P(O)(O)=O)P(O)(O)=O
InChI IdentifierInChI=1S/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
InChI KeyInChIKey=XRASPMIURGNCCH-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as bisphosphonates. These are organic compounds containing two phosphonate groups linked together through a carbon atoms.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassOrganic phosphonic acids and derivatives
Sub ClassBisphosphonates
Direct ParentBisphosphonates
Alternative Parents
Substituents
  • Bisphosphonate
  • N-substituted imidazole
  • Heteroaromatic compound
  • Organophosphonic acid
  • Imidazole
  • Azole
  • Azacycle
  • Organoheterocyclic compound
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organophosphorus compound
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Zoledronate PathwayNot AvailableNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilitySparingly soluble
LogP-4.2
Predicted Properties
PropertyValueSource
Water Solubility3.27 g/LALOGPS
logP-0.93ALOGPS
logP-3.9ChemAxon
logS-1.9ALOGPS
pKa (Strongest Acidic)0.66ChemAxon
pKa (Strongest Basic)6.67ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area153.11 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity52.16 m³·mol⁻¹ChemAxon
Polarizability20.1 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-9120000000-239c3921d9c0513b29bfView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0089-9010000000-350e054fb0333ac6c489View in MoNA
LC-MS/MSLC-MS/MS Spectrum - DI-ESI-qTof , Negativesplash10-000i-0910000000-6c7cee1b60ea3968e2f7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0190000000-d743d302781bf9a387dcView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001l-8910000000-89833833ce5df6ce7fbfView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-9350000000-6a8817aebcf8b58c9872View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-1290000000-3a385a1ab40b3030223aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0fki-4690000000-90b5d47e0913184a3303View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-9100000000-8fed5642f16554892c2dView in MoNA
Toxicity Profile
Route of ExposureIntravenous. Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).
Mechanism of ToxicityThe action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
MetabolismZoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo. Route of Elimination: In 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2. Half Life: 146 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget's Disease.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsThere is no experience of acute overdose. Two patients received zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00399
HMDB IDHMDB14543
PubChem Compound ID68740
ChEMBL IDCHEMBL924
ChemSpider ID61986
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID46557
BioCyc IDZOLEDRONATE
CTD IDNot Available
Stitch IDZoledronic Acid
PDB IDZOL
ACToR IDNot Available
Wikipedia LinkZoledronate
References
Synthesis Reference

Judith Aronhime, Revital Lifshitz-Liron, “Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation.” U.S. Patent US20050054616, issued March 10, 2005.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S: Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov 1;357(18):1799-809. Epub 2007 Sep 17. [17878149 ]
  3. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653-61. [11870242 ]
  4. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005 Jul 7;353(1):99-102; discussion 99-102. [16000365 ]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Poly(a) rna binding
Specific Function:
Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate.
Gene Name:
FDPS
Uniprot ID:
P14324
Molecular Weight:
48275.03 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.00007 uMNot AvailableBindingDB 12578
Inhibitory0.0859 uMNot AvailableBindingDB 12578
IC500.00024 uMNot AvailableBindingDB 12578
IC500.003 uMNot AvailableBindingDB 12578
IC500.0041 uMNot AvailableBindingDB 12578
IC500.1 uMNot AvailableBindingDB 12578
IC500.11 uMNot AvailableBindingDB 50135836
IC500.13 uMNot AvailableBindingDB 12578
IC500.475 uMNot AvailableBindingDB 12578
IC500.4753 uMNot AvailableBindingDB 12578
References
  1. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42. [11160603 ]
  2. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. [17535895 ]
  3. Baulch-Brown C, Molloy TJ, Yeh SL, Ma D, Spencer A: Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. Leuk Res. 2007 Mar;31(3):341-52. Epub 2006 Sep 22. [16996129 ]
  4. Kotsikorou E, Oldfield E: A quantitative structure-activity relationship and pharmacophore modeling investigation of aryl-X and heterocyclic bisphosphonates as bone resorption agents. J Med Chem. 2003 Jul 3;46(14):2932-44. [12825934 ]
  5. Mucha A, Kafarski P, Berlicki L: Remarkable potential of the alpha-aminophosphonate/phosphinate structural motif in medicinal chemistry. J Med Chem. 2011 Sep 8;54(17):5955-80. doi: 10.1021/jm200587f. Epub 2011 Aug 5. [21780776 ]
  6. Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, Oppermann U, Kavanagh KL: Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. J Med Chem. 2008 Apr 10;51(7):2187-95. doi: 10.1021/jm7015733. Epub 2008 Mar 8. [18327899 ]
  7. Simoni D, Gebbia N, Invidiata FP, Eleopra M, Marchetti P, Rondanin R, Baruchello R, Provera S, Marchioro C, Tolomeo M, Marinelli L, Limongelli V, Novellino E, Kwaasi A, Dunford J, Buccheri S, Caccamo N, Dieli F: Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism. J Med Chem. 2008 Nov 13;51(21):6800-7. doi: 10.1021/jm801003y. Epub 2008 Oct 21. [18937434 ]
  8. Lin YS, Park J, De Schutter JW, Huang XF, Berghuis AM, Sebag M, Tsantrizos YS: Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells. J Med Chem. 2012 Apr 12;55(7):3201-15. doi: 10.1021/jm201657x. Epub 2012 Mar 19. [22390415 ]
  9. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
  10. Sanders JM, Gomez AO, Mao J, Meints GA, Van Brussel EM, Burzynska A, Kafarski P, Gonzalez-Pacanowska D, Oldfield E: 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates. J Med Chem. 2003 Nov 20;46(24):5171-83. [14613320 ]
  11. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U: The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34. Epub 2006 May 9. [16684881 ]
References
  1. Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. doi: 10.1002/cmdc.201000016. [20209564 ]
  2. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006 May;38(5):617-27. Epub 2005 Jul 20. [16046206 ]
General Function:
Metal ion binding
Specific Function:
Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
Gene Name:
GGPS1
Uniprot ID:
O95749
Molecular Weight:
34870.625 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory2.7 uMNot AvailableBindingDB 12578
IC5097 uMNot AvailableBindingDB 12578
References
  1. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. [17535895 ]
General Function:
Zinc ion binding
Specific Function:
Seems to specifically activate progelatinase A. May thus trigger invasion by tumor cells by activating progelatinase A on the tumor cell surface. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro-MMP2.
Gene Name:
MMP14
Uniprot ID:
P50281
Molecular Weight:
65893.445 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5012.6 uMNot AvailableBindingDB 12578
References
  1. Tauro M, Laghezza A, Loiodice F, Agamennone M, Campestre C, Tortorella P: Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors. Bioorg Med Chem. 2013 Nov 1;21(21):6456-65. doi: 10.1016/j.bmc.2013.08.054. Epub 2013 Sep 4. [24071448 ]