NAV

Incadronic acid

Identification

Generic Name
Incadronic acid
DrugBank Accession Number
DB06255
Background

Incadronate, or YM-175,6 is a nitrogen containing bisphosphonate. Along with being investigated to treat hypercalcemia of malignancy,7 it has also been investigated in the treatment of myeloma, leukemia, and other cancers.1,3,2,6

Incadronic acid was first described in the literature in 1991.5

Type
Small Molecule
Groups
Experimental
Structure
3D
Similar Structures
Weight
Average: 287.189
Monoisotopic: 287.068761332
Chemical Formula
C8H19NO6P2
Synonyms
  • Cimadronate
  • Incadronate
  • Incadronic acid
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Pharmacology

Indication

Incadronate has been investigated in the treatment of myeloma,1,3 leukemia,2 and other cancers.6 It has also been investigated in patients with hypercalcemia of malignancy.7

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis.8 Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act.8

Osteoclasts mediate resorption of bone.9 When osteoclasts bind to bone they form podosomes, ring structures of F-actin.9 Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption.9

Nitrogen containing bisphosphonates such as incandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate.6 These components are essential for post-translational prenylation of GTP-binding proteins like Rap1.6 The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis.6 incadronate also activated caspases 3, 4, and 7; further contributing to apoptosis.6

TargetActionsOrganism
UFarnesyl pyrophosphate synthase
inhibitor
Humans
UCaspase-3
activator
Humans
UCaspase-4
activator
Humans
UCaspase-7
activator
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Incadronate is not metabolized in rats.7

Route of elimination

Incadronate is 55.1-69.5% eliminated in the urine as the unchanged parent drug.4

Half-life

Incadronate has a biexponential half life. The T1/2α is 0.26-0.40h and the T1/2β is 1.58-1.98h.4

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Integrate drug-drug
interactions in your software
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.
Adefovir dipivoxilThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir dipivoxil is combined with Incadronic acid.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Disodium incadronate7L16W0096A138330-18-4RLIRIVMEKVNVQX-UHFFFAOYSA-L
International/Other Brands
Bisphonal (Astellas) / Yin Fu (Renfu Pharmaceutical)

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aliphatic homomonocyclic compound / Amine / Bisphosphonate / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organophosphonic acid / Organophosphorus compound
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
G5C4M8847E
CAS number
124351-85-5
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

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. [Article]
  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. [Article]
  3. 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. [Article]
  4. 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. [Article]
  5. Kawashima H, Nagao Y, Ishitobi Y, Kinoshita H, Fukushima S: Bisphosphonates increase serum 1,25-dihydroxyvitamin D in rats via stimulating renal production of the hormone. Contrib Nephrol. 1991;91:140-5. doi: 10.1159/000420170. [Article]
  6. Miwa A, Takezako N, Hayakawa H, Hayakawa M, Tominaga S, Yanagisawa K: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. Am J Hematol. 2012 Dec;87(12):1084-8. doi: 10.1002/ajh.23328. Epub 2012 Oct 9. [Article]
  7. Usui T, Tanaka S, Sonoda T, Ozawa Y, Teramura K, Nakamura E, Watanabe T, Higuchi S: Drug disposition of incadronate, a new bisphosphonate, in rats with bone metastases. Xenobiotica. 1997 May;27(5):479-87. doi: 10.1080/004982597240442. [Article]
  8. Russell RG, Watts NB, Ebetino FH, Rogers MJ: Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008 Jun;19(6):733-59. doi: 10.1007/s00198-007-0540-8. [Article]
  9. Murakami H, Takahashi N, Tanaka S, Nakamura I, Udagawa N, Nakajo S, Nakaya K, Abe M, Yuda Y, Konno F, Barbier A, Suda T: Tiludronate inhibits protein tyrosine phosphatase activity in osteoclasts. Bone. 1997 May;20(5):399-404. [Article]
PubChem Compound
3699
PubChem Substance
175427066
ChemSpider
3571
ChEBI
135189
ChEMBL
CHEMBL53950
ZINC
ZINC000001551175
Wikipedia
Incadronic_acid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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-MSsplash10-0a4j-6290000000-a8f7126eac10a0cc53fa
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0190000000-647c573d29c3a2a6c410
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0290000000-51b44be862932e5b7569
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0090000000-b88db17fad64a50d0d0d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-006t-9710000000-be54e7b900a62a61e00b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-4590000000-99b9425810ca8f534e46
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0040-9220000000-5112866c62c0dacbe9d8
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-164.5210766
predicted
DarkChem Lite v0.1.0
[M-H]-142.09602
predicted
DeepCCS 1.0 (2019)
[M+H]+164.6028766
predicted
DarkChem Lite v0.1.0
[M+H]+144.45111
predicted
DeepCCS 1.0 (2019)
[M+Na]+152.45795
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Farnesyl pyrophosphate synthase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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...
Gene Name
FDPS
Uniprot ID
P14324
Uniprot Name
Farnesyl pyrophosphate synthase
Molecular Weight
48275.03 Da
References
  1. Miwa A, Takezako N, Hayakawa H, Hayakawa M, Tominaga S, Yanagisawa K: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. Am J Hematol. 2012 Dec;87(12):1084-8. doi: 10.1002/ajh.23328. Epub 2012 Oct 9. [Article]
Details2. Caspase-3
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
General Function
Phospholipase a2 activator activity
Specific Function
Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' ...
Gene Name
CASP3
Uniprot ID
P42574
Uniprot Name
Caspase-3
Molecular Weight
31607.58 Da
References
  1. Miwa A, Takezako N, Hayakawa H, Hayakawa M, Tominaga S, Yanagisawa K: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. Am J Hematol. 2012 Dec;87(12):1084-8. doi: 10.1002/ajh.23328. Epub 2012 Oct 9. [Article]
Details3. Caspase-4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
General Function
Inflammatory caspase (PubMed:7797510, PubMed:23516580, PubMed:25119034). Essential effector of NLRP3 inflammasome-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:22246630, PubMed:26174085, PubMed:26173988, PubMed:26508369, PubMed:25964352). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, and IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:24879791, PubMed:25964352). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection (PubMed:25121752). In later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which ultimately results in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).
Specific Function
Card domain binding
Gene Name
CASP4
Uniprot ID
P49662
Uniprot Name
Caspase-4
Molecular Weight
43261.87 Da
References
  1. Miwa A, Takezako N, Hayakawa H, Hayakawa M, Tominaga S, Yanagisawa K: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. Am J Hematol. 2012 Dec;87(12):1084-8. doi: 10.1002/ajh.23328. Epub 2012 Oct 9. [Article]
Details4. Caspase-7
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
General Function
Cysteine-type peptidase activity
Specific Function
Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribos...
Gene Name
CASP7
Uniprot ID
P55210
Uniprot Name
Caspase-7
Molecular Weight
34276.48 Da
References
  1. Miwa A, Takezako N, Hayakawa H, Hayakawa M, Tominaga S, Yanagisawa K: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. Am J Hematol. 2012 Dec;87(12):1084-8. doi: 10.1002/ajh.23328. Epub 2012 Oct 9. [Article]

Drug created at March 19, 2008 16:19 / Updated at March 03, 2024 02:32