Structure-activity relationships of non-steroid anti-inflammatory drug 1. Gastric ulcerogenic activity.

Abstract

A comparison was performed of structure with gastric ulcerogenic activity of a range of acidic and one group of non-acidic (tetrazine) non-steroid anti-inflammatory (NSAI) drugs with the object of establishing the physico-chemical properties of these drugs involved in gastric ulceration. The results with non-acetylated salicylate analogues show that an increase in lipophilic properties of 3-substituted salicylates was associated with decreased gastric ulceration. The converse was, however, observed with 4- and 5-substituted salicylates, i.e. increased lipid solubility was associated with enhanced gastric ulceration. 0-Acetylation increased the ulcerogenic activity of all salicylates (except 4-t-butyl derivative). Lipid solubility was also found to influence the gastric ulcerogenic activity of other NSAI drugs in different ways. It is also apparent that electronic factors (which reflect changes in the dissociation constants) and the position of electron-withdrawing substituents on aromatic groups variously influences the ulcerogenic activity in different groups of NSAI drugs. The presence of the carboxylic acid moiety is a major factor in ulcerogenesis by acidic NSAI drugs. Laser Raman spectroscopy of these drugs shows that there is a profound alteration in the frequency of absorption of the carbonyl group in the solid state and in concentrated solutions at pH 6–7. Such changes reflect an intermolecular interaction between the carbonyl and hydroxyl groups of carboxylic acids and suggest that these drugs exist as dimers under these conditions. Dimeric NSAI drugs may initiate gastric damage by the breaking of bonds between the dimers and reformation of bonds between the drugs and membrane phospholipids so disrupting the latter and leading to permeability changes.