Eniluracil is a synthetic pyrimidine analog that acts as an anti-tumor agent. It is a potent inhibitor of thymidylate synthase, an enzyme essential for DNA synthesis. Eniluracil has shown promising anti-cancer activity in preclinical studies, particularly against colorectal cancer. Its synthesis involves a multi-step process that begins with the reaction of 2-chloro-5-nitrobenzaldehyde with 2,4-diamino-6-hydroxypyrimidine. Eniluracil is studied for its potential as a therapeutic agent in various cancers, including colorectal, breast, and lung cancer. Its mechanism of action, along with its ability to overcome drug resistance, has garnered significant research interest.'
eniluracil: structure in first source; inactivates dihydropyrimidine dehydrogenase [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]
| ID Source | ID |
|---|---|
| PubMed CID | 43157 |
| CHEMBL ID | 355200 |
| CHEBI ID | 177783 |
| SCHEMBL ID | 37817 |
| MeSH ID | M0198688 |
| Synonym |
|---|
| CHEBI:177783 |
| 5-ethynyluracil |
| gw-776 |
| eniluracil |
| 776c85 |
| adh-300004 |
| 5-ethynyl-1h-pyrimidine-2,4-dione |
| eniluracil (usan/inn) |
| D03998 |
| 59989-18-3 |
| nsc-687296 |
| nsc687296 |
| eniluracil [usan] |
| gw776c85 |
| compound 776c |
| 2,4(1h,3h)-pyrimidinedione, 5-ethynyl- |
| bdbm50124202 |
| FT-0667865 |
| 776-c-85 |
| CHEMBL355200 , |
| AKOS006240058 |
| AKOS016009479 |
| 5-ethynyl-2,4(1h,3h)pyrimidinedione |
| GEO-02731 |
| unii-2e2w0w5xiu |
| 2e2w0w5xiu , |
| eniluracil [usan:inn:ban] |
| 5-ethynylpyrimidine-2,4(1h,3h)-dione |
| 5-ethynyl-2,4(1h,3h)-pyrimidinedione |
| DB03516 |
| SCHEMBL37817 |
| eniluracil [mi] |
| eniluracil [who-dd] |
| eniluracil [mart.] |
| eniluracil [inn] |
| 5-ethynyl-uracil |
| JOZGNYDSEBIJDH-UHFFFAOYSA-N |
| E1096 |
| DTXSID10208696 |
| 5-ethynyl-2-hydroxypyrimidin-4(3h)-one |
| 5-ethynyl-6-hydroxypyrimidin-2(1h)-one |
| 5-ethynyl-4-hydroxypyrimidin-2(1h)-one |
| 5-ethynyl-2-hydroxypyrimidin-4(1h)-one |
| 5-ethynylpyrimidine-2,4-diol |
| AS-66226 |
| T72682 |
| mfcd00871973 |
| 5-ethynylpyrimidine-2,4(1h,3h)-dione. |
| Q27094456 |
| HY-10533 |
| HMS3745I03 |
| CS-0002630 |
| y3g , |
| ZB1821 |
| A857850 |
Eniluracil (EU) is a potent dihydropyrimidine (DPD) inhibitor, which improves the oral bio-availability of 5-fluorouracil. It may overcome fluoropyrimidine resistance in hepatocellular carcinoma (HCC)
Eniluracil-5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer.
| Excerpt | Reference | Relevance |
|---|---|---|
| "Eniluracil/5-FU has demonstrated efficacy as monotherapy in patients with a variety of solid tumors when given on a 5 or 28-day dosing schedule." | ( Clinical development of eniluracil/fluorouracil: an oral treatment for patients with solid tumors. Hohneker, J; Levin, J, 2000) | 1.34 |
| "Eniluracil-5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. " | ( Multicenter phase II study of a 28-day regimen of orally administered eniluracil and fluorouracil in the treatment of patients with anthracycline- and taxane-resistant advanced breast cancer. Colwell, B; Conklin, HS; Frye, D; Graham, M; Hortobagyi, GN; Levin, J; McGuirt, C; Rivera, E; Somerville, M; Sutton, L, 2002) | 1.99 |
| Excerpt | Reference | Relevance |
|---|---|---|
| "Eniluracil/5-FU/Lv might enable these patients to continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubule-interfering agents." | ( Eniluracil plus 5-fluorouracil and leucovorin: treatment for metastatic breast cancer patients in whom capecitabine treatment rapidly failed. Burdaeva, O; Chang, JC; Kirby, MG; Rivera, E; Semiglazov, V; Spector, T, 2014) | 2.57 |
Pretreatment with eniluracil significantly increases plasma half-life, plasma concentration and oral bioavailability of 5-FU. Treatment was associated with inferior PFS and OS among participants treated with palliative intent for CRC.
To determine the toxicities and. pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil. (5-FU) and leucovorin (LV)
The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-fu. DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed withEnilurACil given alone.
Eniluracil increases the oral bioavailability of 5-FU and results in a switch from hepatic metabolism to renal elimination. Inactivation of DPD using enilurACil is advantageous in that it renders 5-fu orally bioavailable with more predictable pharmacokinetics.
| Excerpt | Reference | Relevance |
|---|---|---|
| " 5-FU oral bioavailability was approximately 100% in rats pretreated with 5-EU." | ( 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Baccanari, DP; Davis, ST; Knick, VC; Spector, T, 1993) | 0.29 |
| "To study the absolute bioavailability and pharmacokinetics of an oral solution of fluorouracil (5-FU) in patients treated with 776C85, an oral inactivator of dihydropyrimidine dehydrogenase (DPD), and to evaluate the feasibility of administering oral 5-FU and 776C85 on a multiple-daily dosing schedule." | ( Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. Adjei, AA; Baker, SD; Donehower, RC; Doucette, M; Grochow, LB; Hohneker, JA; Khor, SP; Noe, DA; Rowinsky, EK; Sartorius, SE; Spector, T, 1996) | 0.29 |
| "Twelve patients completed the bioavailability and pharmacokinetic studies." | ( Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. Adjei, AA; Baker, SD; Donehower, RC; Doucette, M; Grochow, LB; Hohneker, JA; Khor, SP; Noe, DA; Rowinsky, EK; Sartorius, SE; Spector, T, 1996) | 0.29 |
| " Initial clinical data on 5-FU combined with GW776C85 suggest potentially increased antitumor activity in at least some malignancies with tolerable toxicity, as well as several distinct economic and quality-of-life advantages including the following: (1) The possibility of administering 5-FU as an oral drug due to excellent bioavailability of 5-FU following inactivation of DPD; (2) a cost-effective alternative to continuous or protracted infusion of 5-FU without the need for hospitalization or surgical placement of an intravenous access and availability of an ambulatory pump; and (3) potential for less interpatient variation of 5-FU toxicity (e." | ( Improving 5-FU with a novel dihydropyrimidine dehydrogenase inactivator. Diasio, RB, 1998) | 0.3 |
| " Early clinical studies have shown a substantial alteration of the systemic disposition of 5-FU with an increase in 5-FU terminal half-life and have also indicated that EU allows safe oral administration of 5-FU by improving the oral bioavailability of the fluoropyrimidine, which is otherwise too erratic and unpredictable for a drug with such a limited therapeutic window." | ( In vivo effect of 5-ethynyluracil on 5-fluorouracil metabolism determined by 19F nuclear magnetic resonance spectroscopy. Adams, ER; Craig, DJ; Leffert, JJ; Pizzorno, G; Spector, T, 1999) | 0.3 |
| " However, marked intra- and interpatient variability, combined with nonlinear elimination kinetics and erratic oral bioavailability are relative limitations to further development of 5-FU." | ( The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status. Papamichael, D, 1999) | 0.3 |
| " Numerous active 5-FU schedules are in clinical use, but erratic oral bioavailability has historically mandated intravenous administration." | ( Oral therapy for colorectal cancer: how to choose. Damjanov, N; Meropol, NJ, 2000) | 0.31 |
| " However, oral administration of 5-FU has been hampered by incomplete and erratic bioavailability due to substantial variability in the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism." | ( Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase. Kindler, HL; Schilsky, RL, 2000) | 1.75 |
| " In the presence of eniluracil, bioavailability of 5-FU has increased to approximately 100%, the half-life is prolonged to 4 to 6 hours, and systemic clearance is reduced > 20-fold to values comparable the glomerular filtration rate (46 to 58 mL/min/m2)." | ( Pharmacology of fluorinated pyrimidines: eniluracil. Baker, SD, 2000) | 0.9 |
| "The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract." | ( Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma. Hollis, D; Mayer, RJ; Meropol, NJ; Niedzwiecki, D; Schilsky, RL, 2001) | 0.62 |
| " Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%." | ( Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil. Ertel, P; Fleming, GF; Janisch, L; Kastrissios, H; Learned-Coughlin, S; Magnum, S; Mani, S; Ratain, MJ; Schilsky, RL; Shepard, DR; Smith, D, 2002) | 0.83 |
| " Pretreatment with eniluracil significantly increases plasma half-life, plasma concentration and oral bioavailability of 5-FU." | ( Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study. Abbruzzese, JL; Benedetti, JK; George, CS; Giguere, JK; Macdonald, JS; Neubauer, MA; Pruitt, BT; Rothenberg, ML; Seay, TE; Tanaka, MS, 2002) | 0.91 |
| " Concurrent administration of oral eniluracil with oral 5-FU not only increases the bioavailability of 5-FU, owing to elimination of first-pass metabolism, but can change the route of elimination of 5-FU from hepatic metabolism to renal excretion." | ( A study to evaluate the pharmacokinetics of oral 5-fluorouracil and eniluracil after concurrent administration to patients with refractory solid tumours and varying degrees of renal impairment (FUMA1005). Beale, P; Ertel, P; Judson, I; O'Donnell, A; Punt, CJ; Suttle, AB; Van Maanen, L, 2003) | 0.83 |
| "Eniluracil increases the oral bioavailability of 5-FU and results in a switch from hepatic metabolism to renal elimination." | ( A study to evaluate the pharmacokinetics of oral 5-fluorouracil and eniluracil after concurrent administration to patients with refractory solid tumours and varying degrees of renal impairment (FUMA1005). Beale, P; Ertel, P; Judson, I; O'Donnell, A; Punt, CJ; Suttle, AB; Van Maanen, L, 2003) | 2 |
| " Inactivation of DPD using eniluracil is advantageous in that it renders 5-FU orally bioavailable with more predictable pharmacokinetics and blocks one of the major potential mechanisms of 5-FU chemoresistance." | ( Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (GW776C85) in primary and metastatic colorectal cancer. Diasio, RB; Heslin, MJ; Lucas, VS; Owens, J; Shao, L; Weiss, H; Yan, J, 2003) | 0.84 |
Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase. It allows for oral dosing of 5-fluorouracil (5-FU), which avoids the morbidity of continuous infusion 5-FU.
| Class | Description |
|---|---|
| pyrimidone | A pyrimidine carrying one or more oxo substituents. |
| [compound class information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res] | |
| Protein | Taxonomy | Measurement | Average | Min (ref.) | Avg (ref.) | Max (ref.) | Bioassay(s) |
|---|---|---|---|---|---|---|---|
| 5-hydroxytryptamine receptor 2A | Rattus norvegicus (Norway rat) | IC50 (µMol) | 0.0140 | 0.0004 | 0.9086 | 10.0000 | AID56039 |
| Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) | IC50 (µMol) | 0.0140 | 0.0140 | 0.1308 | 0.2200 | AID56039 |
| [prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023] | |||||||
| Process | via Protein(s) | Taxonomy |
|---|---|---|
| protein binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| dihydropyrimidine dehydrogenase (NADP+) activity | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| protein homodimerization activity | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| metal ion binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| flavin adenine dinucleotide binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| NADP binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| 4 iron, 4 sulfur cluster binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| uracil binding | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| [Information is prepared from geneontology information from the June-17-2024 release] | ||
| Process | via Protein(s) | Taxonomy |
|---|---|---|
| cytoplasm | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| cytosol | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| cytosol | Dihydropyrimidine dehydrogenase [NADP(+)] | Homo sapiens (human) |
| [Information is prepared from geneontology information from the June-17-2024 release] | ||
| Assay ID | Title | Year | Journal | Article |
|---|---|---|---|---|
| AID1657002 | Inactivation of bovine liver DHPDHase assessed as Kinact in presence of NADPH | 2020 | Journal of medicinal chemistry, 06-11, Volume: 63, Issue:11 | Acetylene Group, Friend or Foe in Medicinal Chemistry. |
| AID56039 | Inhibitory activity against dihydropyrimidine dehydrogenase (DPD) | 2003 | Bioorganic & medicinal chemistry letters, Mar-10, Volume: 13, Issue:5 | Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine. |
| [information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||||
| Timeframe | Studies, This Drug (%) | All Drugs % |
|---|---|---|
| pre-1990 | 0 (0.00) | 18.7374 |
| 1990's | 39 (34.82) | 18.2507 |
| 2000's | 60 (53.57) | 29.6817 |
| 2010's | 11 (9.82) | 24.3611 |
| 2020's | 2 (1.79) | 2.80 |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be moderate demand-to-supply ratio for research on this compound.
| This Compound (22.61) All Compounds (24.57) |
| Publication Type | This drug (%) | All Drugs (%) |
|---|---|---|
| Trials | 33 (28.95%) | 5.53% |
| Reviews | 42 (36.84%) | 6.00% |
| Case Studies | 2 (1.75%) | 4.05% |
| Observational | 0 (0.00%) | 0.25% |
| Other | 37 (32.46%) | 84.16% |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
| Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
|---|---|---|---|---|---|---|---|
| A Comparative, Multicenter, Open-Label, Randomized, Phase 2 Study of the Safety and Antitumor Activity of Oral Eniluracil + 5 Fluorouracil + Leucovorin Versus Capecitabine Monotherapy in Subjects With Metastatic Breast Cancer [NCT01231802] | Phase 2 | 140 participants (Anticipated) | Interventional | 2011-04-30 | Recruiting | ||
| A Pilot Study of Eniluracil Containing Ointment for Prevention of Hand Foot Syndrome (HRS) Following Capecitabine (Xeloda) [NCT00827580] | Phase 1 | 3 participants (Actual) | Interventional | 2009-01-31 | Terminated | ||
| Phase III Trial Comparing a 28 Day Schedule of Daily Oral 5-FU Plus Eniluracil to Protracted Intravenous Infusion in Previously Untreated Patients With Advanced Colorectal Cancer [NCT00003873] | Phase 3 | 950 participants (Actual) | Interventional | 1999-04-30 | Completed | ||
| A 2-Part Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ADH300004 (Eniluracil) Administered With 5-Fluorouracil (5-FU), and the Pharmacokinetics of 5-FU Given as: 5.0 mg ADH300004 With Escalating Doses of 5-FU Administered Orally 3 Weeks O [NCT00264472] | Phase 1 | 60 participants (Anticipated) | Interventional | 2006-01-31 | Suspended(stopped due to Lack of funds) | ||
| Phase 1 Study of the Evaluation of Dihydropyrimidine Dehydrogenase (DPD), Uridine Phosphorylase (UP), Orotate Phosphoribosyl Transferase (OPRT), and Thymidine Phosphorylase (TP) Activity in Tissue Resected From Subjects Undergoing Planned Resection of Pri [NCT00264446] | Phase 1 | 0 participants | Interventional | Completed | |||
| A Phase 1/2 Study in Subjects With Locally Advanced, Recurrent, or Metastatic Hepatocellular Carcinoma, Evaluating the Safety, and Anti-Tumor Activity of ADH300004 (Eniluracil) With Escalating Doses of 5 Fluorouracil Administered Orally Once Weekly for 3 [NCT00319683] | Phase 1/Phase 2 | 0 participants | Interventional | Terminated(stopped due to Lack of funds) | |||
| A Phase I/II Study of Eniluracil Plus Oral 5-Fluorouracil Combined With Oxaliplatin (FOX-E) in Patients With Previously-Treated Colorectal Cancer [NCT00005050] | Phase 1/Phase 2 | 0 participants | Interventional | 1999-08-31 | Completed | ||
| A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors [NCT00001579] | Phase 1 | 50 participants | Interventional | 1997-06-30 | Completed | ||
| A Phase II Trial of 5-Fluorouracil Plus 776C85 in Patients With Advanced Resistant Colorectal Cancer [NCT00003254] | Phase 2 | 75 participants (Actual) | Interventional | 1998-04-30 | Completed | ||
| Evaluation of Dihydropyrimidine Dehydrogenase (DPD) Activity in Surgically Resected Primary and Metastatic Colorectal Cancer After 48 hr Pretreatment With Eniluracil [NCT00004195] | Phase 2 | 28 participants (Actual) | Interventional | 1998-09-30 | Completed | ||
| A Phase I Study of Concomitant Chemoradiotherapy With 776C85, 5-FU and Hydroxyurea for Patients With Poor Prognosis Oral Cancer [NCT00004901] | Phase 1/Phase 2 | 0 participants | Interventional | 1999-10-31 | Completed | ||
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] | |||||||