[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid

• ChemBase ID: 282
• Molecular Formular: C5H10N2O7P2
• Molecular Mass: 272.089622
• Monoisotopic Mass: 271.99632393
• SMILES: P(=O)(O)(O)C(P(=O)(O)O)(O)Cn1ccnc1
• Canonical SMILES: OP(=O)(C(P(=O)(O)O)(Cn1cncc1)O)O
• InChI: InChI=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)
• InChIKey: XRASPMIURGNCCH-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: [1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid
• IUPAC Traditional name: [1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid; zoledronate
• Brand Name: Zometa; Reclast; Zometa Concentrate; Aclasta
• Synonyms: (1-hydroxy-2-(1h-imidazol-1-yl)-ethylidene)bisphosphonic acid; Zoledronic Acid; Zoledronic acid; ZOL; Zoledronate; Zometa; Zomera; Aclasta and Reclast; Zoledronic Acid

Database IDs

• CAS Number: 118072-93-8
• PubChem SID: 160963745; 46507310
• PubChem CID: 68740

CALCULATED PROPERTIES

JChem

• Acid pKa: 0.657037
• H Acceptors: 8
• H Donor: 5
• LogD (pH = 5.5): -6.7388387
• LogD (pH = 7.4): -7.3929925
• Log P: -3.8511086
• Molar Refractivity: 52.1577 cm^3
• Polarizability: 20.476063 Å^3
• Polar Surface Area: 153.11 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -0.93
• LOG S: -1.92
• Solubility (Water): 3.27e+00 g/l

PROPERTIES

Physical Property

• Solubility: Sparingly soluble; sterile water
• Hydrophobicity(logP): -4.2

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: PKC
• Mechanism of Action: Bone resorption inhibitor; Calcium regulator; Human gamma-lambda T cells activator

Product Information

• Purity: 97%
• Salt Data: Free Base
• Application(s): Prevents skeletal fractures in patients with multiple myeloma and prostate cancer

DETAILS

DrugBank - DB00399

• Drug Groups: approved
• Description: Zoledronate (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.
• Indication: For 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.
• Pharmacology: Zoledronate is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronate is used to prevent osteoporosis and skeletal fractures, particularly in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia, particularly hypercalcemia of malignancy. It can also be helpful for treating pain from bone metastases.
• Toxicity: There 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.
• Affected Organisms: Humans and other mammals
• Biotransformation: Zoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo.
• Absorption: Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).
• Half Life: 146 hours
• Protein Binding: Approximately 22% bound in human plasma, independent of the concentration. However, Canadian product information states binding to human plasma protein is approximately 56%.
• 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.
• Clearance: * Renal cl=3.7 +/- 2.0 L/h
• References: 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 Sep 26;. [Pubmed] ; 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. [Pubmed] ; 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. [Pubmed]
• External Links: Wikipedia; RxList

Selleck Chemicals - S1314

Research Area: Cancer
Biological Activity:
Zoledronic acid, one of the most potent nitrogen-containing BPs(bisphosphonates), induces antiproliferative and apoptotic effects on multiple myeloma cell lines in vitro, by activating protein kinase C, and increases the extracellular calcium concentration.Zoledronic acid and radiation caused a dosedependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 μM and 20μM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). [1]Zoledronate is also known as zometa. It is a treatment for hypercalcemia (high levels of calcium in the blood) caused by tumors. Tumor-induced hypercalcemia is also known as hyper-calcemia of malignancy (HCM). [2]Zoledronic acid also inhibited proliferation of human foetal osteoblastic cell line (hFOB) with an IC50 of 40 μM.In cultures of freshly isolated rabbit and human osteoclasts zoledronic acid (10-100 μM) induced morphological features similar to apoptosis and caspase-3-like activation. Osteoclastogenesis was inhibited in a dose-dependent manner with an IC50 of 15 nM in vitro in cultures of murine bone marrow cells stimulated to form osteoclasts by addition of macrophage-colony stimulating factor and ligand for the receptor activator NF-κB (RANKL).

REFERENCES

• 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 Sep 26;. Pubmed
• 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. Pubmed
• 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. Pubmed
• http://priory.com/pharmol/zoledronic_acid.htm
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