Flufenamic acid

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 443821617

| IUPAC_name = 2-{[3-(Trifluoromethyl)phenyl]amino}benzoic acid

| image = flufenamic acid.png

| image_class = skin-invert-image

| image2 = Flufenamic acid-3D-balls.png

| tradename =

| Drugs.com = {{drugs.com|international|flufenamic-acid}}

| pregnancy_AU =

| pregnancy_category =

| legal_AU = S4

| legal_CA =

| legal_UK =

| legal_US =

| legal_status =

| routes_of_administration = By mouth, topical

| bioavailability =

| protein_bound = extensively

| metabolism = Hydroxylation, glucuronidation

| elimination_half-life = ~3 h

| excretion = 50% urine, 36% feces

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 530-78-9

| ATC_prefix = M01

| ATC_suffix = AG03

| PubChem = 3371

| IUPHAR_ligand = 2447

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB02266

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 3254

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 60GCX7Y6BH

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01581

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 42638

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 23588

| C=14 | H=10 | F=3 | N=1 | O=2

| smiles = FC(F)(F)c1cc(ccc1)Nc2ccccc2C(=O)O

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = LPEPZBJOKDYZAD-UHFFFAOYSA-N

| melting_point = 124

| melting_high = 125

| melting_notes = resolidification and remelting at 134°C to 136°C

| solubility = Practically insoluble in water; soluble in ethanol, chloroform and diethyl ether

}}

Flufenamic acid (FFA) is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs).{{rp|718}} Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of prostaglandins.{{cite journal | journal = LiverTox Database | publisher = U.S. National Institutes of Health (NIH) | url = http://livertox.nih.gov/MefenamicAcid.htm | title = Mefenamic Acid | date = 23 June 2015 | pmid = 31643176 | access-date = 3 July 2015 | quote = (fenamates generally not available in the United States, such as tolfenamic acid and flufenamic acid) }} FFA is known to bind to and reduce the activity of prostaglandin F synthase and activate TRPC6.{{cite web | title=Chemical–Gene Interaction Query: Flufenamic Acid (Homo sapiens) | url=http://ctdbase.org/query.go?type=ixn&chemqt=equals&chem=name%3AFlufenamic+Acid&actionDegreeTypes=increases&actionDegreeTypes=decreases&actionDegreeTypes=affects&actionTypes=activity&actionTypes=binding&geneqt=equals&gene=&pathwayqt=equals&pathway=&taxonqt=equals&taxon=TAXON%3A9606&goqt=equals&go=&sort=chemNmSort&perPage=500&action=Search| work = Comparative Toxicogenomics Database | publisher=North Carolina State University | access-date=July 4, 2015}}

Scientists led by Claude Winder from Parke-Davis invented FFA in 1963, along with fellow members of the class, mefenamic acid in 1961 and meclofenamic acid in 1964.{{cite journal | vauthors = Whitehouse MW | title = Drugs to treat inflammation: a historical introduction | journal = Current Medicinal Chemistry | volume = 12 | issue = 25 | pages = 2931–2942 | date = 2005 | pmid = 16378496 | doi = 10.2174/092986705774462879 | isbn = 9781608052073 }}{{rp|718}}

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

Structure

Flufenamic acid is a highly polymorphic drug molecule with multiple structurally characterized polymorphic modifications.{{Cite journal | vauthors = Serezhkin VN, Savchenkov AV |date=June 3, 2015 |title=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 |journal=Crystal Growth & Design |language=en |volume=15 |issue=6 |pages=2878–2882 |doi=10.1021/acs.cgd.5b00326 |s2cid=100245760 |issn=1528-7483}} It has a unique chemical structure and stands out among fenamates.{{cite journal | vauthors = Mei H, Han J, White S, Graham DJ, Izawa K, Sato T, Fustero S, Meanwell NA, Soloshonok VA | title = Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals | journal = Chemistry: A European Journal | volume = 26 | issue = 50 | pages = 11349–11390 | date = September 2020 | pmid = 32359086 | doi = 10.1002/chem.202000617 | s2cid = 218479815 }} Nowadays, eight polymorphic forms are known that are determined by different conformers,{{cite journal | vauthors = Khodov IA, Belov KV, Krestyaninov MA, Dyshin AA, Kiselev MG | title = Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY | journal = Materials | volume = 16 | issue = 4 | pages = 1524 | date = February 2023 | pmid = 36837153 | pmc = 9961892 | doi = 10.3390/ma16041524 | doi-access = free | bibcode = 2023Mate...16.1524K }}{{cite journal | vauthors = Khodov IA, Belov KV, Huster D, Scheidt HA | title = Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study | journal = Membranes | volume = 13 | issue = 6 | pages = 607 | date = June 2023 | pmid = 37367811 | pmc = 10300900 | doi = 10.3390/membranes13060607 | doi-access = free }} which makes flufenamic acid unique among other low-molecular medicinal compounds.{{Cite journal | vauthors = Delaney SP, Smith TM, Korter TM |date=December 2014 |title=Conformational origins of polymorphism in two forms of flufenamic acid |journal=Journal of Molecular Structure |language=en |volume=1078 |pages=83–89 |doi=10.1016/j.molstruc.2014.02.001|bibcode=2014JMoSt1078...83D }}{{cite journal | vauthors = López-Mejías V, Kampf JW, Matzger AJ | title = Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures | journal = Journal of the American Chemical Society | volume = 134 | issue = 24 | pages = 9872–9875 | date = June 2012 | pmid = 22690822 | pmc = 3634867 | doi = 10.1021/ja302601f | bibcode = 2012JAChS.134.9872L }} A fundamental feature of the structure of flufenamic acid, which has generated significant interest in the design and development of drugs,{{cite journal | vauthors = Pippione AC, Carnovale IM, Bonanni D, Sini M, Goyal P, Marini E, Pors K, Adinolfi S, Zonari D, Festuccia C, Wahlgren WY, Friemann R, Bagnati R, Boschi D, Oliaro-Bosso S, Lolli ML | title = Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid | journal = European Journal of Medicinal Chemistry | volume = 150 | pages = 930–945 | date = April 2018 | pmid = 29602039 | doi = 10.1016/j.ejmech.2018.03.040 | hdl-access = free | s2cid = 4690397 | hdl = 10454/16082 }} is the presence of a trifluoromethyl group. Compounds with fluorine-containing substituents are known to have promising chemical and biological properties,{{cite journal | vauthors = Ojima I | title = Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology | journal = The Journal of Organic Chemistry | volume = 78 | issue = 13 | pages = 6358–6383 | date = July 2013 | pmid = 23614876 | pmc = 3752428 | doi = 10.1021/jo400301u }}{{Cite journal | vauthors = Altomonte S, Zanda M |date=November 2012 |title=Synthetic chemistry and biological activity of pentafluorosulphanyl (SF5) organic molecules |journal=Journal of Fluorine Chemistry |language=en |volume=143 |pages=57–93 |doi=10.1016/j.jfluchem.2012.06.030|hdl=2164/2557 |hdl-access=free }} since such groups often improve the pharmacokinetics and bioavailability of drugs.{{cite journal | vauthors = Hendriks CM, Penning TM, Zang T, Wiemuth D, Gründer S, Sanhueza IA, Schoenebeck F, Bolm C | title = Pentafluorosulfanyl-containing flufenamic acid analogs: Syntheses, properties and biological activities | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 20 | pages = 4437–4440 | date = October 2015 | pmid = 26372652 | pmc = 4599580 | doi = 10.1016/j.bmcl.2015.09.012 }} 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

Until recently, FFA was actively used in medical practice as an analgesic with anti-inflammatory and antipyretic effects.{{cite journal | vauthors = Nechipadappu SK, Tekuri V, Trivedi DR | title = Pharmaceutical Co-Crystal of Flufenamic Acid: Synthesis and Characterization of Two Novel Drug-Drug Co-Crystal | journal = Journal of Pharmaceutical Sciences | volume = 106 | issue = 5 | pages = 1384–1390 | date = May 2017 | pmid = 28185907 | doi = 10.1016/j.xphs.2017.01.033 }} FFA has been proven effective in treating rheumatoid arthritis, osteoarthritis and other inflammation-related diseases.{{cite journal | vauthors = Maestrelli F, Rossi P, Paoli P, De Luca E, Mura P | title = The role of solid state properties on the dissolution performance of flufenamic acid | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 180 | pages = 113058 | date = February 2020 | pmid = 31881398 | doi = 10.1016/j.jpba.2019.113058 | s2cid = 209499101 }} However, despite this, the use of FFA in the United States and other countries {{cite journal | vauthors = Wang Q, Han J, Sorochinsky A, Landa A, Butler G, Soloshonok VA | title = The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine | journal = Pharmaceuticals | volume = 15 | issue = 8 | pages = 999 | date = August 2022 | pmid = 36015147 | pmc = 9416721 | doi = 10.3390/ph15080999 | doi-access = free }} is limited since the compound causes frequent side effects. The rate of gastrointestinal side effects can be as high as 60%,{{cite book | veditors = Aronson JK | chapter-url=https://www.sciencedirect.com/science/article/abs/pii/B9780444537171007551 | doi=10.1016/B978-0-444-53717-1.00755-1 | chapter=Flufenamic acid and meclofenamic acid | title=Meyler's Side Effects of Drugs | edition = 16th | date=2016 | page=361 | publisher=Elsevier | isbn=978-0-444-53716-4 }} manifested as at least one of the following: dyspepsia, nausea, abdominal pain and discomfort, constipation, diarrhoea, flatulence, indigestion, epigastric distress, stomatitits and anorexia. Besides gastrointestinal side effects, the drug can cause headache, dizziness and peripheral oedema.

Side effects

It is not widely used in humans as it has a high rate (30–60%) of gastrointestinal side effects.{{cite book |last=Aronson |first=Jeffrey K. |title=Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs |date=2009 |publisher=Elsevier |isbn=978-0-08-093294-1 }} It is generally not available in the US. It is available in some Asian and European countries as a generic drug.{{cite web |title=International listings for flufenamic acid |url=https://www.drugs.com/international/flufenamic-acid.html |access-date=July 3, 2015 |work=Drugs.com |archive-date=June 30, 2019 |archive-url=https://web.archive.org/web/20190630173637/https://www.drugs.com/international/flufenamic-acid.html |url-status=dead }}

References

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Category:Anthranilic acids

Category:Trifluoromethyl compounds

Category:GABAA receptor positive allosteric modulators

Category:NMDA receptor antagonists