ESTER AND AMIDE PRODRUGS OF IBUPROFEN AND NAPROXEN - SYNTHESIS, ANTIINFLAMMATORY ACTIVITY, AND GASTROINTESTINAL TOXICITY

Ester and amide prodrugs of ibuprofen (1) and naproxen (16) were synthesized and evaluated for anti-inflammatory activity and gastrointestinal toxicity. The chemical structure of the prodrugs was varied in terms of lipophilicity and reactivity toward hydrolysis. Inhibition of acetic acid-induced writhing in mice indicated that prodrugs 7,15,19, and 20 exhibited significantly better activity (p < 0.01) than the parent compounds. The average number of ulcers formed in the gastric mucosa following oral administration of 1 and 16 and prodrugs 5,18, 21, and 22 was determined in rats. All prodrugs, except the glycine amide 21, were significantly less irritating to the gastric mucosa than either 1 or 16.