Synthesis and pharmacological evaluation of amide derivatives of non-steroidal anti-inflammatory drugs

In an effort to produce antirheumatic drugs with an increased therapeutic index, we have explored whether pro-drugs could be targeted to releasable leucocyte amidase(s) that would selectively regenerate an active form of the drug upon hydrolysis in inflammatory exudates. Amides of the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and diclofenac, were prepared by condensing methyl or ethyl esters of various amino acids with the drugs. During a 10 min reaction with peripheral blood leucocytes, blood plasma, or liver extracts, the parent drugs were not regenerated from the amide substrates at 10⁻⁴ M. However, the ester protection of some amino acids was hydrolysed efficiently by leucocyte or liver enzymes, indicating potentially exploitable esterase activities for future targeting studies. Condensation products of indomethacin or diclofenac with phenylalanine were less inhibiting than the parent drug on prostaglandin E₂ release from cultured fibroblasts. However, they were more potent than the corresponding NSAID in competing for formyl-Met-Leu-Phe receptor binding on human neutrophils. This study illustrates practical difficulties encountered while implementing a drug targeting strategy including the selection of a suitable and tissue-specific regenerating enzyme and the residual pharmacological activity of the pro-drug, either similar to or different from the parent drug.