Tmic
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Record Information
Version2.0
Creation Date2009-07-15 20:44:10 UTC
Update Date2014-12-24 20:25:48 UTC
Accession NumberT3D2668
Identification
Common NameRisedronate
ClassSmall Molecule
DescriptionRisedronate is only found in individuals that have used or taken this drug. It is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone.The action of risedronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Risedronate 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
  • Antihypocalcemic Agent
  • Antiresorptive
  • Bisphosphonate
  • Bone Density Conservation Agent
  • Calcium Channel Blocker
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Acide risédroniqe
Acido risedronico
Acidum risedronicum
Actonel
Atelvia
Benet
NE-58095
Ridron
Risedronic acid
Risedronsäure
Chemical FormulaC7H11NO7P2
Average Molecular Mass283.112 g/mol
Monoisotopic Mass283.001 g/mol
CAS Registry Number105462-24-6
IUPAC Name[1-hydroxy-1-phosphono-2-(pyridin-3-yl)ethyl]phosphonic acid
Traditional Namerisedronate
SMILESOC(CC1=CN=CC=C1)(P(O)(O)=O)P(O)(O)=O
InChI IdentifierInChI=1S/C7H11NO7P2/c9-7(16(10,11)12,17(13,14)15)4-6-2-1-3-8-5-6/h1-3,5,9H,4H2,(H2,10,11,12)(H2,13,14,15)
InChI KeyInChIKey=IIDJRNMFWXDHID-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
  • Pyridine
  • Heteroaromatic compound
  • Organophosphonic acid
  • 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
Risedronate 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
Solubility1.04e+01 g/L
LogP-3.6
Predicted Properties
PropertyValueSource
Water Solubility10.4 g/LALOGPS
logP-0.75ALOGPS
logP-3.3ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)0.68ChemAxon
pKa (Strongest Basic)4.91ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area148.18 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity57.12 m³·mol⁻¹ChemAxon
Polarizability21.91 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, Positivesplash10-001l-9030000000-834cccb13596d4a6e4c2View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-00ec-9131000000-85d766b80d3eecd58217View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0f89-0190000000-fd3ef9304911f5ba797fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0f89-7980000000-2508dc22ba77fa4bcee8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-001i-9240000000-2f245ccf75b7681832ceView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0f89-1090000000-882848c0e9a8de518fffView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0w30-3290000000-a1775bd54b8db706bd1fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-003r-9000000000-8ca3758d4566ac31ba50View in MoNA
Toxicity Profile
Route of ExposureRapid absorption (~1 hr) after an oral dose, occurs throughout the upper gastrointestinal tract
Mechanism of ToxicityThe action of risedronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Risedronate 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.
MetabolismNo evidence found for metabolization of risedronate in humans or mammals. Route of Elimination: Risedronate is excreted unchanged primarily via the kidney. Insignificant amounts (<0.1% of intravenous dose) of drug are excreted in the bile in rats. Half Life: 1.5 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 Paget's disease of the bone (osteitis deformans), postmenopausal and glucocorticoid-induced osteoporosis
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects include abdominal pain, anxiety, back pain, belching, bladder irritation, bone disorders and pain, bronchitis, bursitis, cataracts, chest pain, colitis, constipation, depression, diarrhea, difficulty breathing, dizziness, dry eyes, eye infection, flu-like symptoms, gas, headache, high blood pressure, infection, insomnia, itching, joint disorders and pain, leg cramps, muscle pain, muscle weakness, nausea, neck pain, nerve pain, pain, pneumonia, rash, ringing in ears, sinus problems, sore throat, stomach bleeding, stuffy or runny nose, swelling, tendon problems, tumor, ulcers, urinary tract infection, vertigo, vision problems, and weakness.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00884
HMDB IDHMDB15022
PubChem Compound ID5245
ChEMBL IDCHEMBL923
ChemSpider ID5055
KEGG IDC08233
UniProt IDNot Available
OMIM ID
ChEBI ID183772
BioCyc IDRISEDRONATE
CTD IDNot Available
Stitch IDRisedronic acid
PDB IDRIS
ACToR IDNot Available
Wikipedia LinkRisedronate
References
Synthesis Reference

Srinivasa Rao V.N Divvela, Lenin Racha, Sivakumaran Meenakshisunderam, Ramesh Dandala, “Process for the preparation of risedronate sodium hemi-pentahydrate.” U.S. Patent US20070173484, issued July 26, 2007.

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. Drugs.com [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

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
Inhibitory0.00036 uMNot AvailableBindingDB 12576
Inhibitory0.0822 uMNot AvailableBindingDB 12576
IC500.0057 uMNot AvailableBindingDB 12576
IC500.01 uMNot AvailableBindingDB 12576
IC500.011 uMNot AvailableBindingDB 12576
IC500.17 uMNot AvailableBindingDB 12576
IC500.3 uMNot AvailableBindingDB 12576
IC500.4529 uMNot AvailableBindingDB 12576
IC500.86 uMNot AvailableBindingDB 12576
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. Coxon FP, Ebetino FH, Mules EH, Seabra MC, McKenna CE, Rogers MJ: Phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase disrupt the prenylation and membrane localization of Rab proteins in osteoclasts in vitro and in vivo. Bone. 2005 Sep;37(3):349-58. [16006204 ]
  4. Ortiz-Gomez A, Jimenez C, Estevez AM, Carrero-Lerida J, Ruiz-Perez LM, Gonzalez-Pacanowska D: Farnesyl diphosphate synthase is a cytosolic enzyme in Leishmania major promastigotes and its overexpression confers resistance to risedronate. Eukaryot Cell. 2006 Jul;5(7):1057-64. [16835450 ]
  5. 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 ]
  6. Deprele S, Kashemirov BA, Hogan JM, Ebetino FH, Barnett BL, Evdokimov A, McKenna CE: Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies. Bioorg Med Chem Lett. 2008 May 1;18(9):2878-82. doi: 10.1016/j.bmcl.2008.03.088. Epub 2008 Apr 8. [18434151 ]
  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. 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 ]
  10. De Schutter JW, Shaw J, Lin YS, Tsantrizos YS: Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site 'capping' phenyls. Bioorg Med Chem. 2012 Sep 15;20(18):5583-91. doi: 10.1016/j.bmc.2012.07.019. Epub 2012 Jul 24. [22884353 ]
  11. 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 ]
  12. De Schutter JW, Zaretsky S, Welbourn S, Pause A, Tsantrizos YS: Novel bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5781-6. doi: 10.1016/j.bmcl.2010.07.133. Epub 2010 Aug 11. [20801032 ]
  13. 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 ]
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
Inhibitory8300 uMNot AvailableBindingDB 12576
IC50300 uMNot AvailableBindingDB 12576
IC50331.13 uMNot AvailableBindingDB 12576
IC50350 uMNot AvailableBindingDB 12576
References
  1. Singh AP, Zhang Y, No JH, Docampo R, Nussenzweig V, Oldfield E: Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth. Antimicrob Agents Chemother. 2010 Jul;54(7):2987-93. doi: 10.1128/AAC.00198-10. Epub 2010 May 10. [20457823 ]
  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 ]
  3. 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 ]
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 ]