Ester and amide prodrugs of ibuprofen and naproxen: synthesis, anti-inflammatory 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 less than 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.