Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity

Abstract

The methyl and some other esters of acetylsalicylic and salicylic acids and their derivatives were found to have much lower gastric ulcerogenic activity (when assayed in the stress-sensitized rat) compared with their corresponding acids. There was little or no loss in therapeutic potencies of these salicylate esters as determined by assessment of anti-inflammatory activity (against the carrageenan-induced oedema) and antipyretic activity (against yeast-induced fever in rats. The methyl ester of acetylsalicylic acid (=AME) was almost devoid of gastric irritancy/ulcerogenicity (as observed with acetylsalicylic acid) when given orally to pigs for 10 days. AME had appreciable anti-inflammatory activity in the adjuvant-arthritis model and at high doses (200 mg/kg t.i.d.) was without the lethal effects seen with acetylsalicylic acid. Moreover, no toxic effects were seen after long-term administration of 100-1000 mg/kg/day AME for 3-4 months. The results provide further evidence for the hypothesis that the carboxylic acid moiety of salicylates is a major factor in the gastric ulcerogenic activity of these drugs. The methyl esters of these salicylates may be considered as models for the development of pro-drugs and in some cases may be therapeutic alternatives to acetylsalicylic acid or salicylate.