Eniluracil

Identification

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Name
Eniluracil
Accession Number
DB03516  (EXPT03299)
Type
Small Molecule
Groups
Investigational
Description

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).

Structure
Thumb
Synonyms
  • 5-Ethynyluracil
  • Eniluracil
External IDs
776C85 / Compound 776C / GW776C85
Categories
UNII
2E2W0W5XIU
CAS number
59989-18-3
Weight
Average: 136.1082
Monoisotopic: 136.027277382
Chemical Formula
C6H4N2O2
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

Pharmacology

Indication

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

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
UDihydropyrimidine dehydrogenase [NADP(+)]Not AvailableHumans
UAldehyde oxidaseNot AvailableHumans
UXanthine dehydrogenase/oxidase
inhibitor
Humans
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
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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. [PubMed:16466986]
  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. [PubMed:14967434]
  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. [PubMed:12796023]
External Links
KEGG Drug
D03998
PubChem Compound
43157
PubChem Substance
175426856
ChemSpider
39327
BindingDB
50124202
ChEMBL
CHEMBL355200

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCancer, Breast / Malignant Neoplasm of Colon1
2CompletedTreatmentColorectal Cancers2
2Unknown StatusTreatmentMetastatic Breast Cancer (MBC)1
3CompletedTreatmentAdenocarcinoma of the Colon / Adenocarcinoma of the Rectum / Metastatic Colon Cancer / Recurrent Colon Cancer / Recurrent Rectal Cancer / Stage IV Rectal 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)9.5ChemAxon
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-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 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
Pyrimidone / Hydropyrimidine / Vinylogous amide / Heteroaromatic compound / Lactam / Urea / Acetylide / Azacycle / Organic oxide / Organopnictogen compound
show 6 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

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. [PubMed:16466986]
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. [PubMed:8161345]
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. [PubMed:7961725]

Drug created on June 13, 2005 07:24 / Updated on June 04, 2019 05:52