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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| IUPAC_name = 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid
| IUPAC_name = 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid
| image = Brequinar_structure.png
| image = Brequinar Structural Formula V1.svg
<!--Clinical data-->
<!--Clinical data-->
| tradename = Brequinar
| tradename = Brequinar
| legal_US =
| legal_US =
| legal_status =
| legal_status =


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability =
| bioavailability =
| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


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| CAS_number = 96187-53-0
| CAS_number = 96187-53-0
| PubChem = 57030
| PubChem = 57030
| UNII =
| UNII = 5XL19F49H6
| ChemSpiderID =
| ChemSpiderID = 51422
| ChEBI = 177387
| ChEMBL = 38434
| KEGG = D03154
| DrugBank = DB03523


<!--Chemical data-->
<!--Chemical data-->
| C=23 | H=15 | F=2 | N=1 | O=2
| C=23 | H=15 | F=2 | N=1 | O=2
| molecular_weight = 375.4
| SMILES = CC1=C(C2=C(C=CC(=C2)F)N=C1C3=CC=C(C=C3)C4=CC=CC=C4F)C(=O)O
| SMILES = CC1=C(C2=C(C=CC(=C2)F)N=C1C3=CC=C(C=C3)C4=CC=CC=C4F)C(=O)O
| StdInChI=1S/C23H15F2NO2/c1-13-21(23(27)28)18-12-16(24)10-11-20(18)26-22(13)15-8-6-14(7-9-15)17-4-2-3-5-19(17)25/h2-12H,1H3,(H,27,28)
| StdInChI=1S/C23H15F2NO2/c1-13-21(23(27)28)18-12-16(24)10-11-20(18)26-22(13)15-8-6-14(7-9-15)17-4-2-3-5-19(17)25/h2-12H,1H3,(H,27,28)
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}}
}}


'''Brequinar''' ('''DuP-785''') is a drug that acts as a potent and selective inhibitor of the enzyme [[dihydroorotate dehydrogenase]]. It blocks synthesis of [[pyrimidine]] based [[nucleotide]]s in the body and so inhibits cell growth. Brequinar was invented by DuPont Pharmaceuticals in the 1980s.<ref>{{cite journal | vauthors = Dexter DL, Hesson DP, Ardecky RJ, Rao GV, Tippett DL, Dusak BA, Paull KD, Plowman J, DeLarco BM, Narayanan VL | display-authors = 6 | title = Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors | journal = Cancer Research | volume = 45 | issue = 11 Pt 1 | pages = 5563–5568 | date = November 1985 | pmid = 4053030 | url = https://pubmed.ncbi.nlm.nih.gov/4053030 }}</ref> In 2001, Bristol-Myers Squibb acquired DuPont, and in 2017, [https://www.clearcreekbio.com/ Clear Creek Bio] acquired the rights to brequinar from BMS.<ref>{{Cite web |date=May 3, 2022 |title=Bristol Myers Squibb Company History Timeline |url=https://www.bms.com/about-us/our-company/history-timeline.html }}</ref>
'''Brequinar''' ('''DuP-785''') is a drug that acts as a potent and selective inhibitor of the enzyme [[dihydroorotate dehydrogenase]]. It blocks synthesis of [[pyrimidine]] based [[nucleotide]]s in the body and so inhibits cell growth. It has been investigated as an [[immunosuppressant]] for preventing rejection after [[organ transplant]] and also as an anti-cancer drug, but was not accepted for medical use in either application largely due to its narrow therapeutic dose range and severe side effects when dosed inappropriately.<ref>Cramer DV. Brequinar sodium. ''Pediatr Nephrol''. 1995;9 Suppl:S52-5. {{pmid|749248}}</ref><ref>Vyas VK, Ghate M. Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. ''Mini Rev Med Chem''. 2011 Oct;11(12):1039-55. {{doi|10.2174/138955711797247707}} {{pmid|21861807}}</ref> However it continues to be researched both as part of a potential combination therapy for some cancers,<ref>Madak JT, Bankhead A 3rd, Cuthbertson CR, Showalter HD, Neamati N. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. ''Pharmacol Ther''. 2019 Mar;195:111-131. {{doi|10.1016/j.pharmthera.2018.10.012}} {{pmid|30347213}}</ref> or alternatively as an antiparasitic or antiviral drug.<ref>Boschi D, Pippione AC, Sainas S, Lolli ML. Dihydroorotate dehydrogenase inhibitors in anti-infective drug research. ''Eur J Med Chem''. 2019 Dec 1;183:111681. {{doi|10.1016/j.ejmech.2019.111681}} {{pmid|31557612}}</ref><ref>Park JG, Ávila-Pérez G, Nogales A, Blanco-Lobo P, de la Torre JC, Martínez-Sobrido L. Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses. ''J Virol''. 2020 Jan 15. pii: JVI.02149-19. {{doi|10.1128/JVI.02149-19}} {{pmid|31941776}}</ref>


Brequinar has been investigated as an [[immunosuppressant]] for preventing rejection after [[organ transplant]] and also as an anti-cancer drug, but was not accepted for medical use in either application largely due to its narrow therapeutic dose range and severe side effects when dosed inappropriately.<ref name="pmid7492488">{{cite journal | vauthors = Cramer DV | title = Brequinar sodium | journal = Pediatric Nephrology | volume = 9 Suppl | pages = S52-5 | date = 1995 | pmid = 7492488 | doi = 10.1007/bf00867685 | s2cid = 28974570 }}</ref><ref name="pmid30663496">{{cite journal | vauthors = Peters GJ | title = Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor | journal = Nucleosides, Nucleotides & Nucleic Acids | volume = 37 | issue = 12 | pages = 666–678 | date = 2018 | pmid = 30663496 | doi = 10.1080/15257770.2018.1508692 | doi-access = free }}</ref> It has been researched both as part of a potential combination therapy for some cancers,<ref name="pmid21861807">{{cite journal | vauthors = Vyas VK, Ghate M | title = Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors | journal = Mini Reviews in Medicinal Chemistry | volume = 11 | issue = 12 | pages = 1039–55 | date = October 2011 | pmid = 21861807 | doi = 10.2174/138955711797247707 }}</ref><ref name="pmid30347213">{{cite journal | vauthors = Madak JT, Bankhead A, Cuthbertson CR, Showalter HD, Neamati N | title = Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer | journal = Pharmacology & Therapeutics | volume = 195 | pages = 111–131 | date = March 2019 | pmid = 30347213 | doi = 10.1016/j.pharmthera.2018.10.012 | s2cid = 53036782 }}</ref> or alternatively as an [[antiparasitic]],<ref name="pmid31557612">{{cite journal | vauthors = Boschi D, Pippione AC, Sainas S, Lolli ML | title = Dihydroorotate dehydrogenase inhibitors in anti-infective drug research | journal = European Journal of Medicinal Chemistry | volume = 183 | pages = 111681 | date = December 2019 | pmid = 31557612 | doi = 10.1016/j.ejmech.2019.111681 }}</ref> or [[antiviral]] drug.<ref name="pmid31146110">{{cite journal | vauthors = Li SF, Gong MJ, Sun YF, Shao JJ, Zhang YG, Chang HY | title = Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo | journal = Biomedicine & Pharmacotherapy | volume = 116 | pages = 108982 | date = August 2019 | pmid = 31146110 | doi = 10.1016/j.biopha.2019.108982 | doi-access = free }}</ref><ref name="pmid31635418">{{cite journal | vauthors = Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, Koit S, Tenson T, Hukkanen V, Anthonsen MW, Bjoras M, Evander M, Windisch MP, Zusinaite E, Kainov DE | display-authors = 6 | title = Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine | journal = Viruses | volume = 11 | issue = 10 | pages = 964 | date = October 2019 | pmid = 31635418 | pmc = 6832696 | doi = 10.3390/v11100964 | doi-access = free }}</ref><ref name="pmid31941776">{{cite journal | vauthors = Park JG, Ávila-Pérez G, Nogales A, Blanco-Lobo P, de la Torre JC, Martínez-Sobrido L | title = Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses | journal = Journal of Virology | volume = 94| issue = 7| date = January 2020 | pmid = 31941776 | doi = 10.1128/JVI.02149-19 | pmc = 7081893 | doi-access = free }}</ref> Clear Creek Bio is currently developing brequinar as a potential treatment for COVID-19.<ref>{{Cite web |date=November 20, 2020 |title=Clear Creek Bio Doses First Patient in Phase 2 Outpatient Study of Brequinar to Treat COVID-19 |url=https://clearcreekbio.com/clear-creek-bio-doses-first-patient-in-phase-2-outpatient-study-of-brequinar-to-treat-covid-19 }}</ref>

Inhibition of dihydroorotate dehydrogenase activity by brequinar may represent an efficient approach to the elimination of undifferentiated cells for safe [[Pluripotent stem cell|PSC]]-derived differentiated cells based therapies.<ref name="pmid33038285">{{cite journal | vauthors = Kondo, T | title = Selective eradication of pluripotent stem cells by inhibiting DHODH activity | journal = Stem Cells | volume = 39 | issue = 1 | pages = 33–42 | date = October 2021 | pmid = 33038285 | pmc = | doi = 10.1002/stem.3290 | s2cid = 222280648 | hdl = 2115/82146 | hdl-access = free }}</ref>

== See also ==
* [[Leflunomide]] - Clinically used DHODH inhibitor
* [[Methotrexate]] - the most widely used pyrimidine synthesis inhibitor


== References ==
== References ==
{{Reflist}}
{{Reflist}}


[[Category:Antivirals]]
[[Category:Antiviral drugs]]
[[Category:Quinolines]]
[[Category:Biphenyls]]
[[Category:Carboxylic acids]]
[[Category:Organofluorides]]

Latest revision as of 02:48, 27 August 2024

Brequinar
Clinical data
Trade namesBrequinar
Identifiers
  • 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H15F2NO2
Molar mass375.375 g·mol−1
3D model (JSmol)
  • CC1=C(C2=C(C=CC(=C2)F)N=C1C3=CC=C(C=C3)C4=CC=CC=C4F)C(=O)O
  • InChI=1S/C23H15F2NO2/c1-13-21(23(27)28)18-12-16(24)10-11-20(18)26-22(13)15-8-6-14(7-9-15)17-4-2-3-5-19(17)25/h2-12H,1H3,(H,27,28)
  • Key:PHEZJEYUWHETKO-UHFFFAOYSA-N

Brequinar (DuP-785) is a drug that acts as a potent and selective inhibitor of the enzyme dihydroorotate dehydrogenase. It blocks synthesis of pyrimidine based nucleotides in the body and so inhibits cell growth. Brequinar was invented by DuPont Pharmaceuticals in the 1980s.[1] In 2001, Bristol-Myers Squibb acquired DuPont, and in 2017, Clear Creek Bio acquired the rights to brequinar from BMS.[2]

Brequinar has been investigated as an immunosuppressant for preventing rejection after organ transplant and also as an anti-cancer drug, but was not accepted for medical use in either application largely due to its narrow therapeutic dose range and severe side effects when dosed inappropriately.[3][4] It has been researched both as part of a potential combination therapy for some cancers,[5][6] or alternatively as an antiparasitic,[7] or antiviral drug.[8][9][10] Clear Creek Bio is currently developing brequinar as a potential treatment for COVID-19.[11]

Inhibition of dihydroorotate dehydrogenase activity by brequinar may represent an efficient approach to the elimination of undifferentiated cells for safe PSC-derived differentiated cells based therapies.[12]

See also

[edit]

References

[edit]
  1. ^ Dexter DL, Hesson DP, Ardecky RJ, Rao GV, Tippett DL, Dusak BA, et al. (November 1985). "Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors". Cancer Research. 45 (11 Pt 1): 5563–5568. PMID 4053030.
  2. ^ "Bristol Myers Squibb Company History Timeline". May 3, 2022.
  3. ^ Cramer DV (1995). "Brequinar sodium". Pediatric Nephrology. 9 Suppl: S52-5. doi:10.1007/bf00867685. PMID 7492488. S2CID 28974570.
  4. ^ Peters GJ (2018). "Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor". Nucleosides, Nucleotides & Nucleic Acids. 37 (12): 666–678. doi:10.1080/15257770.2018.1508692. PMID 30663496.
  5. ^ Vyas VK, Ghate M (October 2011). "Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors". Mini Reviews in Medicinal Chemistry. 11 (12): 1039–55. doi:10.2174/138955711797247707. PMID 21861807.
  6. ^ Madak JT, Bankhead A, Cuthbertson CR, Showalter HD, Neamati N (March 2019). "Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer". Pharmacology & Therapeutics. 195: 111–131. doi:10.1016/j.pharmthera.2018.10.012. PMID 30347213. S2CID 53036782.
  7. ^ Boschi D, Pippione AC, Sainas S, Lolli ML (December 2019). "Dihydroorotate dehydrogenase inhibitors in anti-infective drug research". European Journal of Medicinal Chemistry. 183: 111681. doi:10.1016/j.ejmech.2019.111681. PMID 31557612.
  8. ^ Li SF, Gong MJ, Sun YF, Shao JJ, Zhang YG, Chang HY (August 2019). "Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo". Biomedicine & Pharmacotherapy. 116: 108982. doi:10.1016/j.biopha.2019.108982. PMID 31146110.
  9. ^ Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, et al. (October 2019). "Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine". Viruses. 11 (10): 964. doi:10.3390/v11100964. PMC 6832696. PMID 31635418.
  10. ^ Park JG, Ávila-Pérez G, Nogales A, Blanco-Lobo P, de la Torre JC, Martínez-Sobrido L (January 2020). "Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses". Journal of Virology. 94 (7). doi:10.1128/JVI.02149-19. PMC 7081893. PMID 31941776.
  11. ^ "Clear Creek Bio Doses First Patient in Phase 2 Outpatient Study of Brequinar to Treat COVID-19". November 20, 2020.
  12. ^ Kondo, T (October 2021). "Selective eradication of pluripotent stem cells by inhibiting DHODH activity". Stem Cells. 39 (1): 33–42. doi:10.1002/stem.3290. hdl:2115/82146. PMID 33038285. S2CID 222280648.
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