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| Formula | C16H12FNO3 |
| Molar mass | 285.274 g·mol−1 |
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Flunoxaprofen, also known as Priaxim, is achiralnonsteroidal anti-inflammatory drug (NSAID). It is closely related tonaproxen, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms ofosteoarthritis andrheumatoid arthritis. The clinical use of flunoxaprofen has ceased due to concerns of potentialhepatotoxicity.
Flunoxaprofen is a two-ringheterocyclic compound derived frombenzoxazole. It also contains afluorine atom and apropanoyl group.
The overall synthesis is similar to that forbenoxaprofen; in this case, para-fluorobenzoyl chloride is used when forming the benzoxazole ring..
ASandmeyer reaction bydiazotisation of 2-(4-aminophenyl)propanenitrile (1) followed by acid hydrolysis leads to the phenol (2), which is nitrated and reduced usingstannous chloride orcatalytic hydrogenation to give the aminophenol (4). Hydrolysis of the nitrile produces thecarboxylic acid (5), which is converted toracemic flunoxaprofen byacylation withp-fluorobenzoyl chloride, followed bycyclisation.[1][2][3][4]
Because flunoxaprofen has limited water-solubility, additional steps must be taken in order to prepare syrups, creams, suppositories, etc. In order to make flunoxaprofen water-soluble, yet still active and efficient, it must be mixed withlysine and then suspended in an organic solvent that is soluble in water. A salt will crystallize upon cooling. The salt must then be filtered out and dried. Pharmacological testing of this now water-soluble compound has shown that it has anti-inflammatory properties equal to flunoxaprofen by itself.[5]
The efficacy and safety of flunoxaprofen has been compared with those ofnaproxen inrheumatoid arthritis patients to show that the two drugs have equivalent therapeutical effects. Both drugs significantly relieve spontaneous pain which occurs both during the day and at night. Both drugs also significantly relieve the pain associated with active and passive motion and aid in relieving morning stiffness. The study also showed both drugs to be equally effective at improvinggrip strength.[6]
Flunoxaprofen is administered as racemate. The absorption and disposition of both enantiomers were studied in 1988. No significant differences between stereoisomers were detected with respect to their absorption and elimination half-lives.[7] However, further studies have shown that the S-enantiomer is the pharmacologically active form of the drug and does not undergo stereoinversion, while R-Flunoxaprofen is pharmacologically activated through biotransformation to the S-enantiomer.[8] This stereospecific chiral inversion is mediated by the FLX-S-Acyl-CoA thioester.[9] Pharmacokinetic studies with stereoselective bioassays have been carried out in different species after racemate dosage (and flunoxaprofen enantiomer derivatives have also been used as chiral fluorescent derivatizing agents to determine the enantiomers of other drug enantiomers in plasma).[10]
It has been shown that the dextrorotatory form is particularly active and has a much highertherapeutic index than some other anti-inflammatories, includingindomethacin anddiclofenac.[5] It has also been shown that flunoxaprofen inhibitsleukotriene rather thanprostaglandin synthesis. This is similar tobenoxaprofen. Flunoxaprofen andbenoxaprofen have been shown to have similar absorption characteristics. However, the distribution and elimination of flunoxaprofen has been shown to be much faster thanbenoxaprofen.[11]
A structural analog of flunoxaprofen isbenoxaprofen. The two drugs are carboxylic acid analogs that form reactive acyl glucuronides. Benoxaprofen has been shown to be involved in rare hepatotoxicity. Because of this, benoxaprofen has been removed from the market. In response to this the clinical use of flunoxaprofen has also stopped, even though studies have shown that flunoxaprofen is less toxic than benoxaprofen.
The toxicity of thesenonsteroidal anti-inflammatory drugs may be related to the covalent modification of proteins in response to the drugs' reactive acyl glucuronides. The reactivity of the acyl glucuronides appears to co-determine the extent of protein binding,[12] as initially proposed by the research group of Benet et al. in 1993.
| pyrazolones / pyrazolidines | |
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| salicylates | |
| acetic acid derivatives and related substances | |
| oxicams | |
| propionic acid derivatives (profens) |
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| n-arylanthranilic acids (fenamates) | |
| COX-2 inhibitors (coxibs) | |
| other | |
| NSAID combinations | |
Key:underline indicates initially developed first-in-class compound of specific group;#WHO-Essential Medicines;†withdrawn drugs;‡veterinary use. | |
