Synthesis and biological evaluation of orally active prodrugs of indomethacin.

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.