Synthesis and biological evaluation of orally active prodrugs (1a-d) of indomethacin are described. Prodrugs 1a-c showed a similar degree of anti-inflammatory activity, and prodrug 1d was found to be less potent than the parent drug indomethacin (1). Ulcer index (UI) data indicated that 1a (UI = 19), 1c (UI = 0), and 1d (UI = 0) were substantially less ulcerogenic and 1b (UI = 62) was more ulcerogenic than parent drug 1 (UI = 47). These prodrugs demonstrated good stability at acidic and basic pH and found to be more lipophilic than parent drug compound 1, indicated by partition coefficients measured in octanol-buffer system at pH 7.4 and 3.0. On the basis of in vivo studies, 1a and 1c compounds were selected for metabolic stability in rat liver microsome (RLM) and rat plasma (RP), and both were found to be enzymatically labile. Prodrugs 1a and 1c emerged as potent anti-inflammatory agents with a lesser potential for ulcer than the parent drug indomethacin.

Diclofenac ester pro drugs (4, 5, 6) were synthesized and evaluated in vitro and in vivo for their potential use for oral delivery, with the aim of obtaining enzymatically labile and less ulceration drugs than the parent drug diclofenac sodium (1a). Prodrugs 4, 5, 6 were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium. Prodrugs 4, 5, 6 rapidly underwent enzymatic hydrolysis to release the parent drug diclofenac in 30-60 min in rat liver microsomes (RLM) and rat plasma (RP). Prodrugs were found to be more lipophilic when the partition coefficient was measured in 1-octanol and buffer system at pH 7.4 and 3.0. Diclofenac prodrugs 4, 5, 6 were found to be crystalline in nature (analyzed by PXRD). Prodrug 4 was found to be a superior candidate for the treatment of chronic inflammatory diseases.

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