A New Anti‐inflammatory Derivative of Imidazole which is Less Ulcerogenic than Indomethacin in Rats

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Abstract
The mechanism of the antiinflammatory activity and ulcerogenicity of (2-dimethylamino-1(2)-methyl) ethyl ester of the 1-(2-carboxyethyl)-2-(p-chlorophenyl)-4,5-bis-(p-methoxyphenyl)-imidazole (A-162-ester) was compared with that of indomethacin in rats and enzymatic preparations derived from other species. A-162-ester was deesterified in plasma to A-162. A-162-ester was .apprx. 3 times less antiinflammatory and .apprx. 17 times less ulcerogenic than indomethacin. A-162-ester, when given orally, decreased prostaglandin I2 (PGI2) biosynthesis by gastric mucosa. The IC50 [median inhibitory concentration] was close to the ulcerogenic ED50. Indomethacin in the same test was 37 times more potent than A-162-ester and the PGI2 inhibition and ulcerogenic dose-response curves for indomethacin were parallel. In other in vitro systems of prostaglandin (PG) biosynthesis, the inhibitory activity of A-162 was comparable to that of indomethacin. Apparently the ulcerogenicity of indomethacin is due to a high affinity of this drug to gastric mucosal wall PG-synthetase which leads to decreased PGI2 formation at this site. The relatively low ulcerogenicity of A-162-ester is most probably due to a lower affinity of this drug to the same site.