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Flufenamic acid

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Flufenamic acid
Clinical data
AHFS/DrugsInternational Drug Names
Routes of
administration		By mouth,topical
ATC code
Legal status
Legal status
  • AU:S4(Prescription only)
Pharmacokineticdata
Protein bindingextensively
MetabolismHydroxylation,glucuronidation
Eliminationhalf-life~3 h
Excretion50% urine, 36% feces
Identifiers
  • 2-{[3-(Trifluoromethyl)phenyl]amino}benzoic acid
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.007.723Edit this at Wikidata
Chemical and physical data
FormulaC14H10F3NO2
Molar mass281.234g·mol−1
3D model (JSmol)
Melting point124 to 125 °C (255 to 257 °F) resolidification and remelting at 134°C to 136°C
Solubility in waterPractically insoluble in water; soluble inethanol,chloroformanddiethyl ethermg/mL (20 °C)
  • FC(F)(F)c1cc(ccc1)Nc2ccccc2C(=O)O
  • InChI=1S/C14H10F3NO2/c15-14(16,17)9-4-3-5-10(8-9)18-12-7-2-1-6-11(12)13(19)20/h1-8,18H,(H,19,20)checkY
  • Key:LPEPZBJOKDYZAD-UHFFFAOYSA-NcheckY
(verify)

Flufenamic acid(FFA) is a member of theanthranilic acid derivatives(or fenamate) class ofnonsteroidal anti-inflammatory drugs(NSAIDs).[1]: 718 Like other members of the class, it is acyclooxygenase(COX) inhibitor, preventing the formation ofprostaglandins.[2]FFA is known to bind to and reduce the activity ofprostaglandin F synthaseand activateTRPC6.[3]

Scientists led by Claude Winder fromParke-Davisinvented FFA in 1963, along with fellow members of the class,mefenamic acidin 1961 andmeclofenamic acidin 1964.[1]: 718 

Although flufenamic acid was at one time informally referred to as "Fluffy" (see history cache), this pet name could also refer toflufenoxine.

Structure

[edit]

Flufenamic acid is a highly polymorphic drug molecule with multiple structurally characterized polymorphic modifications.[4]It has a unique chemical structure and stands out among fenamates.[5]Nowadays, eight polymorphic forms are known that are determined by different conformers,[6][7]which makes flufenamic acid unique among other low-molecular medicinal compounds.[8][9]A fundamental feature of the structure of flufenamic acid, which has generated significant interest in the design and development of drugs,[10]is the presence of a trifluoromethyl group. Compounds with fluorine-containing substituents are known to have promising chemical and biological properties,[11][12]since such groups often improve the pharmacokinetics and bioavailability of drugs.[13]Studies have shown the promise of repositioning flufenamic acid and the use of drugs based on it in the treatment of Bartter syndrome.

Medical uses

[edit]

Until recently, FFA was actively used in medical practice as an analgesic with anti-inflammatory and antipyretic effects.[14]FFA has been proven effective in treating rheumatoid arthritis, osteoarthritis and other inflammation-related diseases.[15]However, despite this, the use of FFA in the United States and other countries[16]is limited since the compound causes frequent side effects. The rate of gastrointestinal side effects can be as high as 60%,[17]manifested as at least one of the following: dyspepsia, nausea, abdominal pain and discomfort, constipation, diarrhoea, flatulence, indigestion, epigastric distress, stomatitits and anorexia.[17]Besides gastrointestinal side effects, the drug can cause headache, dizziness and peripheral oedema.[17]

Side effects

[edit]

It is not widely used in humans as it has a high rate (30–60%) of gastrointestinal side effects.[18]It is generally not available in the US.[2]It is available in some Asian and European countries as ageneric drug.[19]

References

[edit]
  1. ^abWhitehouse MW (2005). "Drugs to treat inflammation: a historical introduction".Current Medicinal Chemistry.12(25): 2931–2942.doi:10.2174/092986705774462879.ISBN9781608052073.PMID16378496.
  2. ^ab"Mefenamic Acid".LiverTox Database.U.S. National Institutes of Health (NIH). June 23, 2015.PMID31643176.RetrievedJuly 3,2015.(fenamates generally not available in the United States, such as tolfenamic acid and flufenamic acid)
  3. ^"Chemical–Gene Interaction Query: Flufenamic Acid (Homo sapiens)".Comparative Toxicogenomics Database.North Carolina State University.RetrievedJuly 4,2015.
  4. ^Serezhkin VN, Savchenkov AV (June 3, 2015). "Application of the Method of Molecular Voronoi–Dirichlet Polyhedra for Analysis of Noncovalent Interactions in Crystal Structures of Flufenamic Acid—The Current Record-Holder of the Number of Structurally Studied Polymorphs".Crystal Growth & Design.15(6): 2878–2882.doi:10.1021/acs.cgd.5b00326.ISSN1528-7483.S2CID100245760.
  5. ^Mei H, Han J, White S, Graham DJ, Izawa K, Sato T, et al. (September 2020). "Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals".Chemistry.26(50): 11349–11390.doi:10.1002/chem.202000617.PMID32359086.S2CID218479815.
  6. ^Khodov IA, Belov KV, Krestyaninov MA, Dyshin AA, Kiselev MG (February 2023)."Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY".Materials.16(4): 1524.Bibcode:2023Mate...16.1524K.doi:10.3390/ma16041524.PMC9961892.PMID36837153.
  7. ^Khodov IA, Belov KV, Huster D, Scheidt HA (June 2023)."Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study".Membranes.13(6): 607.doi:10.3390/membranes13060607.PMC10300900.PMID37367811.
  8. ^Delaney SP, Smith TM, Korter TM (December 2014). "Conformational origins of polymorphism in two forms of flufenamic acid".Journal of Molecular Structure.1078:83–89.Bibcode:2014JMoSt1078...83D.doi:10.1016/j.molstruc.2014.02.001.
  9. ^López-Mejías V, Kampf JW, Matzger AJ (June 2012)."Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures".Journal of the American Chemical Society.134(24): 9872–9875.doi:10.1021/ja302601f.PMC3634867.PMID22690822.
  10. ^Pippione AC, Carnovale IM, Bonanni D, Sini M, Goyal P, Marini E, et al. (April 2018). "Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid".European Journal of Medicinal Chemistry.150:930–945.doi:10.1016/j.ejmech.2018.03.040.hdl:10454/16082.PMID29602039.S2CID4690397.
  11. ^Ojima I (July 2013)."Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology".The Journal of Organic Chemistry.78(13): 6358–6383.doi:10.1021/jo400301u.PMC3752428.PMID23614876.
  12. ^Altomonte S, Zanda M (November 2012). "Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules".Journal of Fluorine Chemistry.143:57–93.doi:10.1016/j.jfluchem.2012.06.030.hdl:2164/2557.
  13. ^Hendriks CM, Penning TM, Zang T, Wiemuth D, Gründer S, Sanhueza IA, et al. (October 2015)."Pentafluorosulfanyl-containing flufenamic acid analogs: Syntheses, properties and biological activities".Bioorganic & Medicinal Chemistry Letters.25(20): 4437–4440.doi:10.1016/j.bmcl.2015.09.012.PMC4599580.PMID26372652.
  14. ^Nechipadappu SK, Tekuri V, Trivedi DR (May 2017). "Pharmaceutical Co-Crystal of Flufenamic Acid: Synthesis and Characterization of Two Novel Drug-Drug Co-Crystal".Journal of Pharmaceutical Sciences.106(5): 1384–1390.doi:10.1016/j.xphs.2017.01.033.PMID28185907.
  15. ^Maestrelli F, Rossi P, Paoli P, De Luca E, Mura P (February 2020). "The role of solid state properties on the dissolution performance of flufenamic acid".Journal of Pharmaceutical and Biomedical Analysis.180:113058.doi:10.1016/j.jpba.2019.113058.PMID31881398.S2CID209499101.
  16. ^Wang Q, Han J, Sorochinsky A, Landa A, Butler G, Soloshonok VA (August 2022)."The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine".Pharmaceuticals.15(8): 999.doi:10.3390/ph15080999.PMC9416721.PMID36015147.
  17. ^abcAronson JK, ed. (2016)."Flufenamic acid and meclofenamic acid".Meyler's Side Effects of Drugs(16th ed.). Elsevier. p. 361.doi:10.1016/B978-0-444-53717-1.00755-1.ISBN978-0-444-53716-4.
  18. ^Aronson JK (2009).Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs.Elsevier.ISBN978-0-08-093294-1.
  19. ^"International listings for flufenamic acid".Drugs.Archived fromthe originalon June 30, 2019.RetrievedJuly 3,2015.
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