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Purity: ≥98%
Eniluracil (also known as 5-Ethynyluracil; GW776C85) is a novel and potent uracil analog and also a mechanism-based irreversible inhibitor of dihydropyrimidine dehydrogenase (DPD), which increases the oral bioavailability of 5-fluorouracil (5-FU) to 100%, facilitating uniform absorption and predictable toxicity.
| Targets |
Eniluracil is a mechanism-based irreversible inhibitor of dihydropyrimidine dehydrogenase (DPD). It binds to the enzyme with a Km of 1.6 µM and inactivates it with a first-order rate constant of 20 min⁻¹ [2]
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| ln Vitro |
Eniluracil enhances the cytotoxicity of 5-FU in human tumor cell lines expressing high levels of DPD, producing a 1- to 5-fold enhancement compared to 5-FU alone. The degree of enhancement correlates with pretreatment DPD activity [2]
Eniluracil itself is not cytotoxic in cell lines [2] |
| ln Vivo |
Rats treated with Eniluracil (5-ethynyluracil) at a dose of 1 mg/kg intraperitoneally once a day for three days experience a significant improvement in FUra (5-fluorouracil) response to treatment, without any side effects or inherent antitumor activity[1].
In rats with colorectal tumors, pretreatment with Eniluracil followed by 5-FU yields a 100% complete and sustained response rate, compared to 13% with 5-FU alone. Eniluracil potentiates the antitumor efficacy and improves the therapeutic index of 5-FU six-fold [2] Eniluracil is neither toxic nor active as a single agent in animals [2] |
| Enzyme Assay |
DPD inactivation by Eniluracil proceeds via a two-step mechanism: initial reversible binding followed by irreversible inactivation. The enzyme is inactivated with a first-order rate constant of 20 min⁻¹ [2]
In rat liver extracts, Eniluracil inhibits more than 99% of DPD activity within minutes of dosing. New DPD is resynthesized with a half-life of 63 hours [2] |
| Cell Assay |
A panel of human tumor cell lines was treated with Eniluracil and 5-FU. Cytotoxicity was assessed and compared to 5-FU alone. Enhancement was observed only in cell lines with high DPD activity [2]
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| Animal Protocol |
Animal/Disease Models: Female Fischer 344/HSD rats (6 to 7 weeks old; 150-200 g) [1].
Doses: 1 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day for 3 days (1 hour before FUra (5-fluorouracil) and an additional 2 days after FUra treatment) Experimental Results: When combined with 3.5 mg/kg FUra, tumor Complete regression persisted for at least 90 days after treatment, but 35 mg/kg FUra alone produced a partial response in 75% of treated animals (tumor regrowth in all of these animals). Rats bearing colorectal tumors were pretreated with Eniluracil followed by 5-FU. Tumor response was evaluated [2] In dogs, co-administration of Eniluracil with 5-FU prevented neurotoxicity associated with high-dose 5-FU [2] In a Phase I trial in human subjects, Eniluracil was administered orally at 3.7 mg/m² on days 1–2, followed by oral or intravenous 5-FU on day 2. Escalating doses of 5-FU (10–25 mg/m²/day) were given on days 2–6 with Eniluracil 3.7 mg/m² on days 1–7 every 28 days [2] |
| ADME/Pharmacokinetics |
Enuracil enables 100% oral bioavailability of 5-fluorouracil in animals and humans [2]. The plasma half-life of enuracil is 4 hours [2]. Enuracil extends the half-life of 5-fluorouracil from 8-22 minutes to 4.4-4.5 hours and reduces its clearance by 20-22 times [2]. When used in combination with enuracil, renal excretion is the main route of clearance of 5-fluorouracil, with 77% of 5-fluorouracil being excreted unchanged in the urine [2]. In patients treated with enuracil, the systemic clearance of 5-fluorouracil is positively correlated with creatinine clearance [2].
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| Toxicity/Toxicokinetics |
In a phase I clinical trial, the dose-limiting toxicity of the 5-day dosing regimen was myelosuppression (neutropenia), while the dose-limiting toxicity of the 28-day dosing regimen was diarrhea [2]. Enuracil irreversibly inhibits DPD; DPD activity returns to normal levels approximately 2 weeks after discontinuation, but serious toxicity may occur if 5-fluorouracil is administered within 4 weeks. It is recommended to wait at least 8 weeks before administering another fluorouracil [2]. Patients with renal insufficiency are at higher risk of toxicity due to reduced clearance of 5-fluorouracil [2].
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| References |
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| Additional Infomation |
Enuracil is a pyrimidinone analogue. Previously developed by GlaxoSmithKline (GSK), it is currently being developed by Adherex Biomedical to enhance the therapeutic value and efficacy of 5-fluorouracil (5-FU). 5-FU is one of the most widely used oncology drugs in the world. It is widely used in the United States, typically as a first- or second-line treatment for various cancers, including colorectal cancer, breast cancer, gastric cancer, head and neck cancer, ovarian cancer, and basal cell carcinoma of the skin. Enuracil is expected to improve the efficacy of 5-FU by enhancing its effectiveness, reducing side effects, and/or making it orally available. Enuracil has received orphan drug designation from the U.S. Food and Drug Administration (FDA) for use in combination with fluorouracil drugs, including 5-FU, to treat hepatocellular carcinoma. Enuracil is an orally effective fluorouracil analogue. Ethyleneuracil inhibits dihydropyrimidine dehydrogenase, the rate-limiting enzyme in the liver that breaks down and inactivates 5-fluorouracil (5-FU). 5-FU can be administered orally when used in combination with acetyluracil.
Drug Indications Used in combination with 5-fluorouracil for the treatment of cancer. Mechanism of Action Normally, 5-FU is rapidly broken down in the body by an enzyme called dihydropyrimidine dehydrogenase (DPD). Enuracil irreversibly inhibits DPD, thereby significantly slowing down the breakdown of 5-fluorouracil (5-FU) and prolonging the contact time between tumor cells and the drug. The development of enuracil aims to overcome the problem of unstable oral bioavailability of 5-FU due to differences in DPD activity[2]. It may overcome 5-FU resistance mediated by DPD overexpression[2]. Phase II clinical trials for colorectal cancer, breast cancer, liver cancer, and pancreatic cancer have been completed; results of phase III clinical trials for colorectal cancer and pancreatic cancer are pending analysis[2]. Compared with continuous intravenous infusion, enuracil has predictable pharmacokinetics and good toxicity profile, and is therefore considered a promising oral chemotherapy option[2]. |
| Molecular Formula |
C6H4N2O2
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|---|---|
| Molecular Weight |
136.1082
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| Exact Mass |
136.027
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| CAS # |
59989-18-3
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| PubChem CID |
43157
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.39g/cm3
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| Melting Point |
320 °C(dec.)
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| Index of Refraction |
1.589
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| LogP |
-0.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
10
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| Complexity |
269
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C(C#C[H])=C([H])N([H])C(N1[H])=O
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| InChi Key |
JOZGNYDSEBIJDH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C6H4N2O2/c1-2-4-3-7-6(10)8-5(4)9/h1,3H,(H2,7,8,9,10)
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| Chemical Name |
5-ethynyl-1H-pyrimidine-2,4-dione
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| Synonyms |
5-Ethynyluracil; GW-776C85; GW 776C85; GW776C85
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~16.67 mg/mL (~122.47 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (15.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (15.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (15.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 7.3470 mL | 36.7350 mL | 73.4700 mL | |
| 5 mM | 1.4694 mL | 7.3470 mL | 14.6940 mL | |
| 10 mM | 0.7347 mL | 3.6735 mL | 7.3470 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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