Highly selective inhibitors of thromboxane synthetase. 1. Imidazole derivatives

Article abstract of DOI:10.1021/jm00142a005

The structure-activity relationships of imidazole derivatives as inhibitors of thromboxane (TX) synthetase were investigated. Introduction of various substituents (e.g., one or two methyl groups, a halogen atom, a methylidene group, unsaturated bonds, or a phenylene group) into the α position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum for the inhibitory potency on TX synthetase in the region of 8.5-9.0 A. Among the tested imidazole derivatives, 1-(7-carboxy-7-methyl-2-octynyl)imidazole, 4-[3-(1-imidazolyl)-propyl]benzoic acid, and (E)-4-(1-imidazolylmethyl)cinnamic acid and its α-methyl analogue showed the highest potency with an IC₅₀ in the range of 10^-8 to 10^-9 M. Inhibition by these derivatives was highly selective for the TX synthetase, since other enzymes such as fatty acid cyclo-oxygenase and prostacyclin synthetase were not affected.