Fenamates

The relatively low potency of aspirin in overcoming the symptoms of inflammatory diseases has led to a continuing search for new antiinflammatory agents. Although many more potent agents have been introduced to clinical practice, most of these elicit some side effects that limit their use. Derivatives of iv-aryl anthra-nillic acids have provided a series of quite effective antiinflammatory drugs, the so-called fenamic acids. 

Ullman condensation of m-trifluoromethylaniline (13) with o-iodobenzoic acid in the presence of copper-bronze affords flu-fenamic acid (14). An analogous reaction of o-chlorobenzolc acid with 2,3-dimethylaniline (15) gives mefenamic acid (16) meclofenamic acid (18) is obtained by Ullman condensation employing 2,6-dlchloro-3-methylaniline (17). 

Replacement of one of the benzene rings by pyridine in the fenamic acid-type analgesics leads to an agent with full pharmacologic activity. Treatment of the N-oxide of nicotinic acid with phosphorus trichloride followed by hydrolysis of the acid... 

Flufenamic acid (162) is a reasonably well-established NSAID (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassiuni salt with the hydroxyethyl ethyl ether of ethylenechlo-rohydrin affords the latendated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

A number of compounds activate TRPA1 without any apparent ability to form covalent adducts, including nonelectrophilic fenamate nonsteroidal anti-inflammatory drugs (NSAIDs), such as flufenamic acid (17, FFA), niflumic acid (18, NFA), and mefenamic acid (19, MFA) [13]. Phenols such as thymol (20) and 2-ferf-butyl-5-methylphenol (21) have been shown to activate human TRPA1 with micromolar EC50 values in stably transfected HEK293 cells [14]. 

H. I. (2002) Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes. European Journal of Pharmacology, 452, 269-277. 

Two compounds of the fenamate class of antiinflammatory drugs are marketed in the United States. Mefenamic acid (Ponstel) is indicated only for analgesia and primary dysmenorrhea when therapy will not exceed 1 week. Meclofenamate sodium (Meclomen) is prescribed for rheumatoid arthritis and osteoarthritis. 

The fenamates show no clear superiority in antiinflammatory activity and may produce more adverse effects than other NSAIDs. Diarrhea may be severe enough to necessitate discontinuation of drug use. Other adverse GI reactions include nausea, vomiting,... 

Brooks, C. D. W., Craig, R. A., Kolasa, T., Stewart, A. O. Iminoxy derivatives of fenamates as inhibitors of prostaglandin biosynthesis (Abbott Laboratories) US 5863946,1999. 

Chemical Name 2-Amino-3-benzoylbenzeneacetic acid sodium salt Common Name Amfenac sodium, Fenamate Structural Formula ... 

Synonym Difenamide, Dimid, Dymid, Enide, Fenam, Rideon... 

Tryptophan—a single strong binding site that coincides with or overlaps the binding site for NphOAc, small fatty acid anions, benzodiazepines, fenamic acids, naproxen, ibuprofen,... 

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