NAV

Eniluracil

Identification

Generic Name
Eniluracil
DrugBank Accession Number
DB03516
Background

Eniluracil, which was previously under development by GlaxoSmithKline (GSK), is being developed by Adherex to enhance the therapeutic value and effectiveness of 5-fluorouracil (5-FU), one of the world’s most widely-used oncology agents. 5-FU is widely used in the U.S. and is often first or second line therapy for a variety of cancers including colorectal, breast, gastric, head and neck, ovarian and basal cell cancer of the skin. Eniluracil could improve 5-FU by increasing its effectiveness, reducing its side effects and/or making it orally available. Eniluracil has received Orphan Drug status from the FDA for the treatment of hepatocellular cancer in combination with fluoropyrimidines (including 5-FU).

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 136.1082
Monoisotopic: 136.027277382
Chemical Formula
C6H4N2O2
Synonyms
  • 5-Ethynyluracil
  • Eniluracil
External IDs
  • 776C85
  • Compound 776C
  • GW776C85
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Pharmacology

Indication

For the treatment of cancer in combination with 5-fluorouracil.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Eniluracil is an orally active dihydropyrimidine dehydrogenase (DPD) inhibitor, designed to enhance activity of chemotaxic agents. It is under investigation by Adherex, under license from GlaxoSmithKline, for the treatment of cancer in combination with 5-fluorouracil (5-FU).

Mechanism of action

Normally, 5-FU is rapidly broken down in the body by an enzyme known as dihydropyrimidine dehydrogenase (DPD). Eniluracil irreversibly inhibits DPD, thereby substantially slowing the breakdown of 5-FU and prolonging exposure of the tumor cells to the drug.

TargetActionsOrganism
UAldehyde oxidaseNot AvailableHumans
UXanthine dehydrogenase/oxidase
inhibitor
Humans
UDihydropyrimidine dehydrogenase [NADP(+)]Not AvailableHumans
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.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrimidones. These are compounds that contain a pyrimidine ring, which bears a ketone. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Pyrimidones
Alternative Parents
Hydropyrimidines / Vinylogous amides / Heteroaromatic compounds / Ureas / Lactams / Azacyclic compounds / Acetylides / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds
show 2 more
Substituents
Acetylide / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Lactam / Organic nitrogen compound / Organic oxide / Organic oxygen compound
show 6 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
2E2W0W5XIU
CAS number
59989-18-3
InChI Key
JOZGNYDSEBIJDH-UHFFFAOYSA-N
InChI
InChI=1S/C6H4N2O2/c1-2-4-3-7-6(10)8-5(4)9/h1,3H,(H2,7,8,9,10)
IUPAC Name
5-ethynyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
SMILES
O=C1NC=C(C#C)C(=O)N1

References

General References
  1. Czito BG, Hong TJ, Cohen DP, Petros WP, Tyler DS, Pappas TN, Yu D, Lee CG, Lockhart AC, Morse MA, Fernando N, Hurwitz HI: A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract. Cancer Invest. 2006 Feb;24(1):9-17. [Article]
  2. Czito BG, Hong TJ, Cohen DP, Tyler DS, Lee CG, Anscher MS, Ludwig KA, Seigler HF, Mantyh C, Morse MA, Lockhart AC, Petros WP, Honeycutt W, Spector NL, Ertel PJ, Mangum SG, Hurwitz HI: A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):779-85. [Article]
  3. Yip D, Karapetis C, Strickland AH, Steer C, Holford C, Knight S, Harper P: A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies. Ann Oncol. 2003 Jun;14(6):864-6. [Article]
KEGG Drug
D03998
PubChem Compound
43157
PubChem Substance
175426856
ChemSpider
39327
BindingDB
50124202
ChEMBL
CHEMBL355200
ZINC
ZINC000000005467
PDBe Ligand
Y3G
PDB Entries
7ljs / 7ljt / 7lju

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAdenocarcinoma of Colon / Rectal Adenocarcinoma / Recurrent Colon Cancer / Recurrent Rectal Cancer / Stage IV Colon Cancer / Stage IV Rectal Cancer1
2CompletedTreatmentColorectal Cancer2
2Unknown StatusTreatmentMetastatic Breast Cancer1
1TerminatedTreatmentBreast Cancer / Colon Cancer1

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 Solubility0.254 mg/mLALOGPS
logP-0.91ALOGPS
logP-0.82Chemaxon
logS-2.7ALOGPS
pKa (Strongest Acidic)8.54Chemaxon
pKa (Strongest Basic)-6.4Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area58.2 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity33.39 m3·mol-1Chemaxon
Polarizability12.05 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.888
Blood Brain Barrier+0.9797
Caco-2 permeable-0.8105
P-glycoprotein substrateNon-substrate0.7936
P-glycoprotein inhibitor INon-inhibitor0.9305
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.9228
CYP450 2C9 substrateNon-substrate0.7322
CYP450 2D6 substrateNon-substrate0.8668
CYP450 3A4 substrateNon-substrate0.779
CYP450 1A2 substrateNon-inhibitor0.6875
CYP450 2C9 inhibitorNon-inhibitor0.9586
CYP450 2D6 inhibitorNon-inhibitor0.9655
CYP450 2C19 inhibitorNon-inhibitor0.9685
CYP450 3A4 inhibitorNon-inhibitor0.9468
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9883
Ames testNon AMES toxic0.9024
CarcinogenicityNon-carcinogens0.9454
BiodegradationReady biodegradable0.5346
Rat acute toxicity1.6987 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9667
hERG inhibition (predictor II)Non-inhibitor0.9515
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-MSsplash10-000i-8900000000-dd78f7511ef0363019ea
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-1900000000-8ccff8ca76cd5473fe45
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-3900000000-d15a33add30422c4a7af
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ftu-9300000000-9cc4449a208346aaf6ac
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9000000000-6b2f88776be86ced1c11
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gvt-9000000000-e264ecd46a8e729a7bc2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01ox-9000000000-0298a69bf5d1bb0e0be0
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]-128.1131104
predicted
DarkChem Lite v0.1.0
[M-H]-124.170044
predicted
DeepCCS 1.0 (2019)
[M+H]+129.0766104
predicted
DarkChem Lite v0.1.0
[M+H]+127.05307
predicted
DeepCCS 1.0 (2019)
[M+Na]+128.6056104
predicted
DarkChem Lite v0.1.0
[M+Na]+135.90393
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Aldehyde oxidase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Xanthine dehydrogenase activity
Specific Function
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N-methylphthalazinium, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal...
Gene Name
AOX1
Uniprot ID
Q06278
Uniprot Name
Aldehyde oxidase
Molecular Weight
147916.735 Da
References
  1. Porter DJ, Harrington JA, Almond MR, Lowen GT, Zimmerman TP, Spector T: 5-ethynyl-2(1H)-pyrimidinone: aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase. Biochem Pharmacol. 1994 Mar 29;47(7):1165-71. [Article]
Details2. Xanthine dehydrogenase/oxidase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xanthine oxidase activity
Specific Function
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...
Gene Name
XDH
Uniprot ID
P47989
Uniprot Name
Xanthine dehydrogenase/oxidase
Molecular Weight
146422.99 Da
References
  1. Porter DJ: Reaction of 5-ethynyluracil with rat liver xanthine oxidase. J Biol Chem. 1994 Nov 11;269(45):27932-40. [Article]
Details3. Dihydropyrimidine dehydrogenase [NADP(+)]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein homodimerization activity
Specific Function
Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
Gene Name
DPYD
Uniprot ID
Q12882
Uniprot Name
Dihydropyrimidine dehydrogenase [NADP(+)]
Molecular Weight
111400.32 Da
References
  1. Czito BG, Hong TJ, Cohen DP, Petros WP, Tyler DS, Pappas TN, Yu D, Lee CG, Lockhart AC, Morse MA, Fernando N, Hurwitz HI: A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract. Cancer Invest. 2006 Feb;24(1):9-17. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 14, 2023 19:03