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Flufenamic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of; administration	By mouth, topical
ATC code	M01AG03 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only);
Pharmacokinetic data
Protein binding	extensively
Metabolism	Hydroxylation, glucuronidation
Elimination half-life	~3 h
Excretion	50% urine, 36% feces
Identifiers
	IUPAC name 2-{[3-(Trifluoromethyl)phenyl]amino}benzoic acid;
CAS Number	530-78-9 ;
PubChem CID	3371;
IUPHAR/BPS	2447;
DrugBank	DB02266 ;
ChemSpider	3254 ;
UNII	60GCX7Y6BH;
KEGG	D01581 ;
ChEBI	CHEBI:42638 ;
ChEMBL	ChEMBL23588 ;
CompTox Dashboard (EPA)	DTXSID7023063 ;
ECHA InfoCard	100.007.723
Chemical and physical data
Formula	C14H10F3NO2
Molar mass	281.234 g·mol−1
3D model (JSmol)	Interactive image;
Melting point	124 to 125 °C (255 to 257 °F) resolidification and remelting at 134°C to 136°C
Solubility in water	Practically insoluble in water; soluble in ethanol, chloroform and diethyl ether mg/mL (20 °C)
	SMILES FC(F)(F)c1cc(ccc1)Nc2ccccc2C(=O)O;
	InChI 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) ; Key:LPEPZBJOKDYZAD-UHFFFAOYSA-N ;
	(verify)

Flufenamic acid (FFA) is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs).^[1]^: 718 Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of prostaglandins.^[2] FFA is known to bind to and reduce the activity of prostaglandin F synthase and activate TRPC6.^[3]

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.^[1]^: 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.^[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

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

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 a generic drug.^[19]

References

^ ^a ^b Whitehouse MW (2005). "Drugs to treat inflammation: a historical introduction". Current Medicinal Chemistry. 12 (25): 2931–2942. doi:10.2174/092986705774462879. ISBN 9781608052073. PMID 16378496.
^ ^a ^b "Mefenamic Acid". LiverTox Database. U.S. National Institutes of Health (NIH). June 23, 2015. PMID 31643176. Retrieved July 3, 2015. (fenamates generally not available in the United States, such as tolfenamic acid and flufenamic acid)
^ "Chemical–Gene Interaction Query: Flufenamic Acid (Homo sapiens)". Comparative Toxicogenomics Database. North Carolina State University. Retrieved July 4, 2015.
^ 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. ISSN 1528-7483. S2CID 100245760.
^ 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. PMID 32359086. S2CID 218479815.
^ 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. PMC 9961892. PMID 36837153.
^ 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. PMC 10300900. PMID 37367811.
^ 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.
^ 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. Bibcode:2012JAChS.134.9872L. doi:10.1021/ja302601f. PMC 3634867. PMID 22690822.
^ 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. PMID 29602039. S2CID 4690397.
^ 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. PMC 3752428. PMID 23614876.
^ 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.
^ 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. PMC 4599580. PMID 26372652.
^ 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. PMID 28185907.
^ 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. PMID 31881398. S2CID 209499101.
^ 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. PMC 9416721. PMID 36015147.
^ ^a ^b ^c Aronson 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. ISBN 978-0-444-53716-4.
^ Aronson JK (2009). Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Elsevier. ISBN 978-0-08-093294-1.
^ "International listings for flufenamic acid". Drugs.com. Archived from the original on June 30, 2019. Retrieved July 3, 2015.