A new anti-inflammatory derivative of imidazole which is less ulcerogenic than indomethacin in rats.
The mechanism of the anti-inflammatory 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 found to be deesterified in plasma to A-162. A-162-ester was about 3 times less anti-inflammatory and about 17 times less ulcerogenic than indomethacin. A-162-ester, when given orally, decreased prostaglandin I2 (PGI2) biosynthesis by gastric mucosa. The IC50 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. It is concluded that the ulcerogenicity of indomethacin results from a high affinity of this drug to gastric mucosal wall PG-synthetase which leads to decreased PGI3 formation at this site. The relatively low ulcerogenicity of A-162-ester most probable results from a lower affinity of this drug to the same site.
D000818:Animals; D000893:Anti-Inflammatory Agents; D001682:Biological Availability; D055598:Chemical Phenomena; D002621:Chemistry; D004353:Drug Evaluation, Preclinical; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D007213:Indomethacin / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced*
D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D011464:Epoprostenol; D007213:Indomethacin