NAV

OXI-4503

Identification

Generic Name
OXI-4503
DrugBank Accession Number
DB05143
Background

OXI-4503 is investigated in clinical trials for treating cancer/tumors. OXI-4503 is a solid. OXI-4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. OXI-4503 (combretastatin A1 di-phosphate / CA1P) is a unique and highly potent, dual-mechanism vascular disrupting agent (VDA). In addition, however, preclinical data demonstrates that OXI-4503 is metabolized by oxidative enzymes (e.g., tyrosinase and peroxidases), which are elevated in many solid tumors and tumor infiltrates, to an orthoquinone chemical species that has direct cytotoxic effects on tumor cells. Preclinical studies have demonstrated that OXI-4503 has (i) single-agent activity against a range of xenograft tumor models; and (ii) synergistic or additive effects when incorporated in various combination regimens with chemotherapy, molecularly-targeted therapies (including tumor-angiogenesis inhibitors), and radiation therapy.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 492.31
Monoisotopic: 492.058650144
Chemical Formula
C18H22O12P2
Synonyms
  • CA1P
  • Combretastatin A-1 bis(phosphate)
  • Combretastatin A1 diphosphate
  • OXI4503
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Pharmacology

Indication

Investigated for use/treatment in cancer/tumors (unspecified).

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Contraindications & Blackbox Warnings
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Pharmacodynamics

OXi4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. In addition, however, preclinical data demonstrates that OXi4503 is metabolized by oxidative enzymes (e.g., tyrosinase and peroxidases), which are elevated in many solid tumors and tumor infiltrates, to an orthoquinone chemical species that has direct cytotoxic effects on tumor cells.

Mechanism of action

OXi4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. It induced the shutdown of tumor blood vessels and affected peripheral tumor regions less than central regions.

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

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
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interactions in your software
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium acetateCalcium acetate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium carbonateCalcium carbonate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium chlorideCalcium chloride can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium citrateCalcium citrate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
OXI-4503 dipotassiumQ9F7QEH36F1014615-46-3IQYUGENRXZHYER-XNOMRPDFSA-L

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Phenyl phosphates / Styrenes / Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / Organic oxides / Hydrocarbon derivatives
Substituents
Alkyl aryl ether / Anisole / Aromatic homomonocyclic compound / Aryl phosphate / Aryl phosphomonoester / Benzenoid / Ether / Hydrocarbon derivative / Methoxybenzene / Monocyclic benzene moiety
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
JH6Z94GLUD
CAS number
288847-35-8
InChI Key
GSOXMQLWUDQTNT-WAYWQWQTSA-N
InChI
InChI=1S/C18H22O12P2/c1-25-13-8-7-12(16(29-31(19,20)21)18(13)30-32(22,23)24)6-5-11-9-14(26-2)17(28-4)15(10-11)27-3/h5-10H,1-4H3,(H2,19,20,21)(H2,22,23,24)/b6-5-
IUPAC Name
[3-methoxy-2-(phosphonooxy)-6-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]phosphonic acid
SMILES
[H]\C(=C(/[H])C1=C(OP(O)(O)=O)C(OP(O)(O)=O)=C(OC)C=C1)C1=CC(OC)=C(OC)C(OC)=C1

References

General References
  1. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C: Alterations in vascular architecture and permeability following OXi4503 treatment. Anticancer Drugs. 2008 Jan;19(1):17-22. [Article]
  2. Hokland SL, Horsman MR: The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization. Int J Hyperthermia. 2007 Nov;23(7):599-606. [Article]
  3. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C: Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis. Anticancer Res. 2007 Jul-Aug;27(4B):2317-23. [Article]
  4. Salmon HW, Siemann DW: Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Clin Cancer Res. 2006 Jul 1;12(13):4090-4. [Article]
PubChem Compound
6918546
PubChem Substance
175426952
ChemSpider
5293743
BindingDB
50236033
ChEMBL
CHEMBL1205402
ZINC
ZINC000003994214

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentMetastatic Cancer1
1CompletedTreatmentSolid Tumors1
1TerminatedTreatmentAcute Myeloid Leukemia / Myelodysplastic Syndrome1
1, 2Unknown StatusTreatmentAcute Myeloid Leukemia / Myelodysplastic Syndrome1

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 Solubility0.0268 mg/mLALOGPS
logP1.76ALOGPS
logP1.77Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)1.31Chemaxon
pKa (Strongest Basic)-4.3Chemaxon
Physiological Charge-4Chemaxon
Hydrogen Acceptor Count10Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area170.44 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity113.07 m3·mol-1Chemaxon
Polarizability43.31 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8178
Blood Brain Barrier+0.9392
Caco-2 permeable+0.5621
P-glycoprotein substrateNon-substrate0.6563
P-glycoprotein inhibitor IInhibitor0.5894
P-glycoprotein inhibitor IINon-inhibitor0.7451
Renal organic cation transporterNon-inhibitor0.9072
CYP450 2C9 substrateNon-substrate0.7647
CYP450 2D6 substrateNon-substrate0.7938
CYP450 3A4 substrateSubstrate0.5659
CYP450 1A2 substrateInhibitor0.5726
CYP450 2C9 inhibitorNon-inhibitor0.7198
CYP450 2D6 inhibitorNon-inhibitor0.9068
CYP450 2C19 inhibitorInhibitor0.5589
CYP450 3A4 inhibitorInhibitor0.505
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6137
Ames testNon AMES toxic0.8531
CarcinogenicityNon-carcinogens0.6756
BiodegradationNot ready biodegradable0.7566
Rat acute toxicity2.6950 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7806
hERG inhibition (predictor II)Non-inhibitor0.8709
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 MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-01ox-0000900000-4fb51dfd73417f2b6e3a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03fr-9000000000-fc7d0b7166bbe341d34c
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9000000000-41da059149283996aa4d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-5019800000-c76ccd6631ccf01e35fb
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9000000000-fc2e910c437ef0829068
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001l-2039300000-1033ed06f6b95be6402f
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]-193.62865
predicted
DeepCCS 1.0 (2019)
[M+H]+195.93784
predicted
DeepCCS 1.0 (2019)
[M+Na]+201.85054
predicted
DeepCCS 1.0 (2019)

Drug created at October 21, 2007 22:23 / Updated at June 12, 2020 16:52