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
- Weight
- Average: 287.189
Monoisotopic: 287.068761332 - Chemical Formula
- C8H19NO6P2
- Synonyms
- Cimadronate
- Incadronate
- Incadronic acid
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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- 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
Target Actions Organism UFarnesyl pyrophosphate synthase inhibitorHumans UCaspase-3 activatorHumans UCaspase-4 activatorHumans UCaspase-7 activatorHumans - 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAceclofenac The risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Incadronic acid. Acemetacin The risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Incadronic acid. Acetylsalicylic acid The risk or severity of gastrointestinal bleeding can be increased when Acetylsalicylic acid is combined with Incadronic acid. Acyclovir The risk or severity of nephrotoxicity and hypocalcemia can be increased when Acyclovir is combined with Incadronic acid. Adefovir dipivoxil The risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir dipivoxil is combined with Incadronic acid. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Disodium incadronate 7L16W0096A 138330-18-4 RLIRIVMEKVNVQX-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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- External Links
- PubChem Compound
- 3699
- PubChem Substance
- 175427066
- ChemSpider
- 3571
- ChEBI
- 135189
- ChEMBL
- CHEMBL53950
- ZINC
- ZINC000001551175
- Wikipedia
- Incadronic_acid
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count
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
Property Value Source Water Solubility 12.5 mg/mL ALOGPS logP -0.06 ALOGPS logP -1.4 Chemaxon logS -1.4 ALOGPS pKa (Strongest Acidic) -1.1 Chemaxon pKa (Strongest Basic) 5.57 Chemaxon Physiological Charge -2 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 5 Chemaxon Polar Surface Area 127.09 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 61.77 m3·mol-1 Chemaxon Polarizability 25.08 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.9677 Blood Brain Barrier + 0.61 Caco-2 permeable - 0.6668 P-glycoprotein substrate Non-substrate 0.6742 P-glycoprotein inhibitor I Non-inhibitor 0.9645 P-glycoprotein inhibitor II Non-inhibitor 0.9852 Renal organic cation transporter Non-inhibitor 0.9306 CYP450 2C9 substrate Non-substrate 0.7403 CYP450 2D6 substrate Non-substrate 0.8094 CYP450 3A4 substrate Non-substrate 0.7024 CYP450 1A2 substrate Non-inhibitor 0.8029 CYP450 2C9 inhibitor Non-inhibitor 0.8975 CYP450 2D6 inhibitor Non-inhibitor 0.9162 CYP450 2C19 inhibitor Non-inhibitor 0.8689 CYP450 3A4 inhibitor Non-inhibitor 0.9708 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9856 Ames test Non AMES toxic 0.6935 Carcinogenicity Non-carcinogens 0.8743 Biodegradation Ready biodegradable 0.6431 Rat acute toxicity 2.0444 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6875 hERG inhibition (predictor II) Non-inhibitor 0.926
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0a4j-6290000000-a8f7126eac10a0cc53fa Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0190000000-647c573d29c3a2a6c410 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0290000000-51b44be862932e5b7569 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-0090000000-b88db17fad64a50d0d0d Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-006t-9710000000-be54e7b900a62a61e00b Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000i-4590000000-99b9425810ca8f534e46 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0040-9220000000-5112866c62c0dacbe9d8 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 164.5210766 predictedDarkChem Lite v0.1.0 [M-H]- 142.09602 predictedDeepCCS 1.0 (2019) [M+H]+ 164.6028766 predictedDarkChem Lite v0.1.0 [M+H]+ 144.45111 predictedDeepCCS 1.0 (2019) [M+Na]+ 152.45795 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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]
- 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
- 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]
- 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
- 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]
- 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
- 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 November 03, 2023 23:48