Pamidronate (T3D2665)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (3)XML
Targets (3)
Record Information
Version2.0
Creation Date2009-07-15 20:42:44 UTC
Update Date2014-12-24 20:25:48 UTC
Accession NumberT3D2665
Identification
Common NamePamidronate
ClassSmall Molecule
DescriptionPamidronate is only found in individuals that have used or taken this drug.Pamidronate, marketed as pamidronate disodium pentahydrate under the brand name Aredia, is a bisphosphonate. The mechanism of action of pamidronate is inhibition of bone resorption. Pamidronate adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. Pamidronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and 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.
Compound Type
  • Amine
  • Anti-Inflammatory Agent
  • Antineoplastic Agent
  • Bisphosphonate
  • Bone Density Conservation Agent
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
Acide pamidronique
Acido pamidronico
Acidum pamidronicum
Aminomux
Aredia
Pamidronate Disodium
Pamidronic acid
Pamimed
Ribodroat
Chemical FormulaC3H11NO7P2
Average Molecular Mass235.070 g/mol
Monoisotopic Mass235.001 g/mol
CAS Registry Number40391-99-9
IUPAC Name(3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid
Traditional Namepamidronate
SMILESNCCC(O)(P(O)(O)=O)P(O)(O)=O
InChI IdentifierInChI=1S/C3H11NO7P2/c4-2-1-3(5,12(6,7)8)13(9,10)11/h5H,1-2,4H2,(H2,6,7,8)(H2,9,10,11)
InChI KeyInChIKey=WRUUGTRCQOWXEG-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
  • Organophosphonic acid
  • 1,3-aminoalcohol
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Primary amine
  • Organophosphorus compound
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Amine
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Pamidronate PathwayNot AvailableNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility1.58e+01 g/L
LogP-4.7
Predicted Properties
PropertyValueSource
Water Solubility15.8 g/LALOGPS
logP-1.4ALOGPS
logP-4.5ChemAxon
logS-1.2ALOGPS
pKa (Strongest Acidic)0.67ChemAxon
pKa (Strongest Basic)9.86ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area161.31 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity42.62 m³·mol⁻¹ChemAxon
Polarizability17.34 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-9010000000-c609aeb84dc854acef5e2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0fl0-9530000000-3dcc66dec182929ad44c2017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00kr-0590000000-70afb6f8f6bd4fa8dc0c2016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0f80-4900000000-d984e8b630279adf91172016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00lr-9220000000-23665351b55d845211712016-08-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0f89-2590000000-b548987abea1368137052016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0uyi-5940000000-2fa45eefdeb643c061942016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-003r-9000000000-57907eeacb268739b1252016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001r-9070000000-60834fd1c274bf3a378e2021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-0690000000-46aca5e6c3a2ca2b76cf2021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-9200000000-4a70bd6f6de42e1622e12021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00lr-0090000000-2ee377abd33f38d7b1d92021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-01q9-9020000000-13ae78878ab3e85dd77f2021-09-25View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03di-9000000000-818b4c1881e12ac6419e2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-25View Spectrum
Toxicity Profile
Route of ExposureParenteral (intravenous). Plasma concentration rises rapidly upon IV administration.
Mechanism of ToxicityThe mechanism of action of pamidronate is inhibition of bone resorption. Pamidronate adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. Pamidronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and 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.
MetabolismPamidronate is not metabolized and is exclusively eliminated by renal excretion. Route of Elimination: Pamidronate is not metabolized and is exclusively eliminated by renal excretion. Half Life: The mean ± SD elimination half-life is 28 ± 7 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesPamidronate is in a class of drugs called bisphosphonates. Pamidronate reduces breakdown of the bones. Pamidronate is used in the treatment of Paget's disease of bone; to reduce high levels of calcium in the blood associated with malignancy (cancer); and to reduce the breakdown of bone due to metastases of breast cancer or multiple myeloma. For the treatment of moderate or severe hypercalcemia associated with malignancy
Minimum Risk LevelNot Available
Health EffectsRare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis, and one case of uveitis upon separate rechallenges.
SymptomsSide effects include an allergic reaction, kidney problems, seizures, low levels of calcium, magnesium, or phosphorus in the blood
TreatmentIf overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous calcium. (6)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00282
HMDB IDHMDB14427
PubChem Compound ID4674
ChEMBL IDCHEMBL834
ChemSpider ID4512
KEGG IDC07395
UniProt IDNot Available
OMIM ID
ChEBI ID160401
BioCyc IDPAMIDRONATE
CTD IDNot Available
Stitch IDPamidronic acid
PDB ID210
ACToR IDNot Available
Wikipedia LinkPamidronate
References
Synthesis Reference

Edward C. Shinal, “Method for preparation of disodium pamidronate.” U.S. Patent US6268524, issued February, 1988.

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. Zarychanski R, Elphee E, Walton P, Johnston J: Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol. 2006 Jan;81(1):73-5. [16369966 ]
  3. Omega Laboratory (2009). Material Safety Data Sheet for Pamidronate Disodium Omega. [Link]
  4. Drugs.com [Link]
  5. RxList: The Internet Drug Index (2009). [Link]
  6. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Farnesyl pyrophosphate synthase
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
Inhibitory0.0559 uMNot AvailableBindingDB 12581
Inhibitory0.3314 uMNot AvailableBindingDB 12581
IC500.2 uMNot AvailableBindingDB 12581
IC500.3532 uMNot AvailableBindingDB 12581
IC501.862 uMNot AvailableBindingDB 12581
IC501.9 uMNot AvailableBindingDB 12581
IC501.932 uMNot AvailableBindingDB 12581
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000 Jan 1;373(1):231-41. [10620343 ]
  3. 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 ]
  4. Riebeling C, Forsea AM, Raisova M, Orfanos CE, Geilen CC: The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. Br J Cancer. 2002 Jul 29;87(3):366-71. [12177810 ]
  5. Notarnicola M, Messa C, Cavallini A, Bifulco M, Tecce MF, Eletto D, Di Leo A, Montemurro S, Laezza C, Caruso MG: Higher farnesyl diphosphate synthase activity in human colorectal cancer inhibition of cellular apoptosis. Oncology. 2004;67(5-6):351-8. [15713990 ]
  6. Zhang PL, Lun M, Siegelmann-Danieli N, Blasick TM, Brown RE: Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy. Ann Clin Lab Sci. 2004 Summer;34(3):263-70. [15487700 ]
  7. Szabo CM, Matsumura Y, Fukura S, Martin MB, Sanders JM, Sengupta S, Cieslak JA, Loftus TC, Lea CR, Lee HJ, Koohang A, Coates RM, Sagami H, Oldfield E: Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. J Med Chem. 2002 May 23;45(11):2185-96. [12014956 ]
  8. 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 ]
  9. 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 ]
  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 ]
Target Details
2. Geranylgeranyl pyrophosphate synthase
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
IC50180 uMNot AvailableBindingDB 12581
IC50181.97 uMNot AvailableBindingDB 12581
References
  1. Szabo CM, Matsumura Y, Fukura S, Martin MB, Sanders JM, Sengupta S, Cieslak JA, Loftus TC, Lea CR, Lee HJ, Koohang A, Coates RM, Sagami H, Oldfield E: Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. J Med Chem. 2002 May 23;45(11):2185-96. [12014956 ]
  2. K-M Chen C, Hudock MP, Zhang Y, Guo RT, Cao R, No JH, Liang PH, Ko TP, Chang TH, Chang SC, Song Y, Axelson J, Kumar A, Wang AH, Oldfield E: Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem. 2008 Sep 25;51(18):5594-607. doi: 10.1021/jm800325y. [18800762 ]
Target Details
3. Hydroxylapatite
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 ]