Incadronic acid

Identification

Logo pink
Are you a
new drug developer?
Contact us to learn more about our customized products and solutions.
Name
Incadronic acid
Accession Number
DB06255
Type
Small Molecule
Groups
Experimental
Description

Incadronic acid is a third generation bisphosphonate which can suppress bone resorption by osteoclasts. It is used to treat hypercalcemia, and bone disorders associated with malignancy and osteoporosis. In rats with induced hypercalcemia, incadronate has been found to be 46 times more potent than pamidronate and 11 times more potent than aledronate.

Incadronate has also been found to have anti-tumor effects in mice. In rat models of breast cancer, bisphosphonate treatment has been shown to inhibit the progression and development of bone metastases and reduce tumor burden in vivo. It has also been recognized as a potential treatment for adult T-cell leukaemia which is characterized by hypercalcemia and tumor-induced osteolysis. 2 Incadronate, as well as other nitrogen containing bisphosphonates, such as aledronate and minodronate, have been found to induce apoptosis of hematopoietic tumor cells. In vitro human myeloma cells have undergone apoptosis when exposed to incadronate. 5

When combined with Tipifarnib, a potent farnesyl transferase inhibitor which can suppress the growth of myeloma cells, growth suppression of myeloma cells in vitro is intensified. 6 Because of these findings Incadronate is being investigated as a treatment for multiple myeloma, a B-cell malignancy associated with bone loss.

Incadronate is available by prescription only, and is not marked is the United States, UK, Canada, or Australia. It is an approved treatment for malignancy-associated hypercalcemia (MAH) in Japan.8

Structure
Thumb
Synonyms
  • Cimadronate
  • Incadronate
Product Ingredients
IngredientUNIICASInChI Key
Disodium incadronate7L16W0096A138330-18-4RLIRIVMEKVNVQX-UHFFFAOYSA-L
International/Other Brands
Bisphonal (Astellas) / Yin Fu (Renfu Pharmaceutical)
Categories
UNII
G5C4M8847E
CAS number
124351-85-5
Weight
Average: 287.189
Monoisotopic: 287.068761332
Chemical Formula
C8H19NO6P2
InChI Key
LWRDQHOZTAOILO-UHFFFAOYSA-N
InChI
InChI=1S/C8H19NO6P2/c10-16(11,12)8(17(13,14)15)9-7-5-3-1-2-4-6-7/h7-9H,1-6H2,(H2,10,11,12)(H2,13,14,15)
IUPAC Name
[(cycloheptylamino)(phosphono)methyl]phosphonic acid
SMILES
OP(O)(=O)C(NC1CCCCCC1)P(O)(O)=O

Pharmacology

Indication

For the treatment of hypercalcemia associated with malignant disease.

Pharmacodynamics
Not Available
Mechanism of action

Incadronate suppresses bone resorption by inhibiting osteoclasts. Incadronate was found to induce apoptosis in myeloma cells by S-phase cell cycle arrest via inhibition of the mevalonate (MVA) pathway and activation of the MAPK pathway. [1] Similarly, in studies looking at the potential role of incadronate as a treatment for adult T-cell leukemia, incadronate has been shown to inhibit the growth of T-cell lines infected with the human T-cell leukaemia virus by inducing apoptosis and S-phase cell cycle arrest by inhibiting the mevalonate pathway.

Nitrogen containing bisphosphonates such as incandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the Ras signaling pathway, as well as activating the Bim-mediated mitochondrial intrinsic apoptotic pathway. [5] They also induce apoptosis by inhibiting the prenylation of small G-proteins. [5]

Absorption

Pharmacokinetic studies in patients with MAH have indicated linear pharmacokinetics with intravenous administration. [8]

In studies comparing absorption of incadronate in healthy volunteers verses volunteers with MAH plasma levels have been similar at 2 h, however at 8 h the plasma levels are three times higher in patients with MAH. This can be explained by the decrease in renal function experienced by patients with MAH. Notably, however, the plasma levels of incadronate are not as high as expected based on the reduction in renal clearance. This indicates that patients with hypercalcemia may experience enhanced bone uptake of the drug. [8]

Volume of distribution

Incadronate rapidly relocalizes to bone due to its high affinity for mineralized bone. [4] Due to its incorporation into bone marrow osteoclasts the concentration of incadronate in the bone marrow is high. [4]

Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Renally eliminated. [8]

Half life

0.26-0.40 h (t1/2 alpha) and 1.58 - 1.98 h (t1/2 beta). [8]

Clearance

60% renal clearance. [8] Changes in renal clearance may affect the pharmacokinetics of incadronate.

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AceclofenacThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Incadronic acid.
AcemetacinThe risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Incadronic acid.
Acetylsalicylic acidThe risk or severity of gastrointestinal bleeding can be increased when Acetylsalicylic acid is combined with Incadronic acid.
AcyclovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Incadronic acid.
AdefovirThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir is combined with Incadronic acid.
Adefovir dipivoxilThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir dipivoxil is combined with Incadronic acid.
AlclofenacThe risk or severity of gastrointestinal bleeding can be increased when Alclofenac is combined with Incadronic acid.
Alendronic acidThe risk or severity of hypocalcemia can be increased when Alendronic acid is combined with Incadronic acid.
AlmasilateThe serum concentration of Incadronic acid can be decreased when it is combined with Almasilate.
AlminoprofenThe risk or severity of gastrointestinal bleeding can be increased when Alminoprofen is combined with Incadronic acid.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

    Learn more
  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

    Learn more
  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

    Learn more
Food Interactions
Not Available

References

General References
  1. Iguchi T, Miyakawa Y, Yamamoto K, Kizaki M, Ikeda Y: Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway. Cell Signal. 2003 Jul;15(7):719-27. [PubMed:12742232]
  2. Ishikawa C, Matsuda T, Okudaira T, Tomita M, Kawakami H, Tanaka Y, Masuda M, Ohshiro K, Ohta T, Mori N: Bisphosphonate incadronate inhibits growth of human T-cell leukaemia virus type I-infected T-cell lines and primary adult T-cell leukaemia cells by interfering with the mevalonate pathway. Br J Haematol. 2007 Feb;136(3):424-32. [PubMed:17233845]
  3. Kim SB, Lee JS, Kim HT, Im YH, Kim TW, Ryoo BY, Park YH, Park JO, Park K, Katoh H, Yamamoto M: Clinical evaluation of incadronate in korean patients with malignancy-associated hypercalcemia: An open-label, multicenter study. Curr Ther Res Clin Exp. 2007 May;68(3):193-204. doi: 10.1016/j.curtheres.2007.06.004. [PubMed:24683210]
  4. Matsuo A, Shuto T, Hirata G, Satoh H, Matsumoto Y, Zhao H, Iwamoto Y: Antiinflammatory and chondroprotective effects of the aminobisphosphonate incadronate (YM175) in adjuvant induced arthritis. J Rheumatol. 2003 Jun;30(6):1280-90. [PubMed:12784404]
  5. Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW: Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol. 2003 Jul;170(1):246-52. [PubMed:12796698]
  6. Ochiai N, Yamada N, Uchida R, Fuchida S, Okano A, Okamoto M, Ashihara E, Inaba T, Shimazaki C: Nitrogen-containing bisphosphonate incadronate augments the inhibitory effect of farnesyl transferase inhibitor tipifarnib on the growth of fresh and cloned myeloma cells in vitro. Leuk Lymphoma. 2005 Nov;46(11):1619-25. [PubMed:16236616]
  7. Shipman CM, Croucher PI, Russell RG, Helfrich MH, Rogers MJ: The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res. 1998 Dec 1;58(23):5294-7. [PubMed:9850051]
  8. Usui T, Oiso Y, Tomita A, Ogata E, Uchida T, Ikeda K, Watanabe T, Higuchi S: Pharmacokinetics of incadronate, a new bisphosphonate, in healthy volunteers and patients with malignancy-associated hypercalcemia. Int J Clin Pharmacol Ther. 1997 Jun;35(6):239-44. [PubMed:9208339]
External Links
PubChem Compound
3699
PubChem Substance
175427066
ChemSpider
3571
ChEBI
135189
ChEMBL
CHEMBL53950
Wikipedia
Incadronic_acid

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility12.5 mg/mLALOGPS
logP-0.06ALOGPS
logP-1.4ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)-1.1ChemAxon
pKa (Strongest Basic)5.57ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area127.09 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity61.77 m3·mol-1ChemAxon
Polarizability25.08 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9677
Blood Brain Barrier+0.61
Caco-2 permeable-0.6668
P-glycoprotein substrateNon-substrate0.6742
P-glycoprotein inhibitor INon-inhibitor0.9645
P-glycoprotein inhibitor IINon-inhibitor0.9852
Renal organic cation transporterNon-inhibitor0.9306
CYP450 2C9 substrateNon-substrate0.7403
CYP450 2D6 substrateNon-substrate0.8094
CYP450 3A4 substrateNon-substrate0.7024
CYP450 1A2 substrateNon-inhibitor0.8029
CYP450 2C9 inhibitorNon-inhibitor0.8975
CYP450 2D6 inhibitorNon-inhibitor0.9162
CYP450 2C19 inhibitorNon-inhibitor0.8689
CYP450 3A4 inhibitorNon-inhibitor0.9708
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9856
Ames testNon AMES toxic0.6935
CarcinogenicityNon-carcinogens0.8743
BiodegradationReady biodegradable0.6431
Rat acute toxicity2.0444 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6875
hERG inhibition (predictor II)Non-inhibitor0.926
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as bisphosphonates. These are organic compounds containing two phosphonate groups linked together through a carbon atoms.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Organic phosphonic acids and derivatives
Sub Class
Bisphosphonates
Direct Parent
Bisphosphonates
Alternative Parents
Organic phosphonic acids / Dialkylamines / Organopnictogen compounds / Organophosphorus compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Bisphosphonate / Organophosphonic acid / Secondary amine / Secondary aliphatic amine / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative / Organophosphorus compound
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
Not Available

Drug created on March 19, 2008 10:19 / Updated on June 04, 2019 06:22