Anti-inflammatory arylacetic acids

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

An important pathway of 0-glucuronidation is the formation of acyl-glucuronides. Substrates are anti-inflammatory arylacetic acids and aliphatic acids such as valproic acid (13). These metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins." Thus, acyl glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxihcation. 

This information was used to design bucloxic acid, fenbufene and furobufene, which are all bioprecursor forms of anti-inflammatory arylacetic acids (Fig. 33.36). For all these compounds the bioactivation takes place through a multistep process implying reductive, oxidative and hydration-dehydration sequences. 

Gund P, Shen TY. A modei for the prostagiandin synthetase cyciooxygenation site and its inhibition by anti-inflammatory arylacetic acids. J Med Chem 1977 20 1146-1152. 

Cleavage at the benzylic position has likewise been observed in a variety of (hetero) aromatic derivatives such as chloramphenicol (Sch. 13) (31) or methotrexate (32). An important case is that of the decarboxylation of arylacetic or arylpropionic acids used as non-steroidal anti-inflammatory agents (Sch. 14) (33-35). 

The arylacetic acid derivative group of agents has received the most intensive attention for new clinical candidates. As u group, they show high analgesic potency in addition to their anti-inflammatory activity. 

FLUORO-2-PHENYLPROPANE, represents another route to a number of monofluorinated compounds. The mono-C-methylation of arylacetonitriles and methyl arylacetates by dimethyl carbonate as a route to 2-arylpropionic acids is exemplified by the synthesis of 2-PHENYLPROPIONIC ACID, the simplest member of an important class of anti-inflammatory agents. 

Arylacetic Acids and Esters. - The anti-inflammatory properties of these compounds continues to stimulate new work in this area existing approaches have been summarisd in a review. 3 Another version of the well established [1.2]-aryl migration route to phenylacetic acids consists simply of treatment of the... 

Like the arylacetic acids the arylpropionic acid analogues also exhibit potent anti-inflammatory properties besides usual antipyretic and analgesic characteristics. A few examples of this category of compounds are discussed here, flurbiprofen ketoprofen indoprofen fenoprofen calcium. 

The reeent intensive quest for non-steroid anti-inflammatory drugs and arylacetic acids in particular offer a brighter seope that the naphthalene acetic acid analogues might turn out to be the leading compounds of an extensive series of promising clinical agents. Example Naproxen. 

The sunscreen agent 2-ethyUiexyl p-methoxycinnamate has been produced on a pilot plant scale by a Heck coupling of p-methoxyphenyl iodide with 2-ethylhexyl acrylate using palladium on charcoal as a catalyst [622]. Naproxen, a member of the arylacetic acid family of nonsteroidal anti-inflammatory drugs... 

New and Experimental Agents - Arylalkanoic Acids - An in iressive number of arylacetic and aryl-alkanoic acids with significant anti-inflammatory properties have been reported during the year, ale ICI 5UU5O, l) is apparently clinically effective in rheumatoid arthritis. Activity has also been reported for 5-p-chlorophenyl-2-furanacetic acid Acids II and III have activity comparable to that of phenylbutazone in acute and... 

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