Highly selective inhibitors of thromboxane synthetase. 1. Imidazole derivatives

Abstract

The structure-activity relationships of imidazole derivatives as inhibitors of human thromboxane (TX) synthetase were investigated. Introduction of various substituents (e.g., 1 or 2 methyl groups, a halogen atom, a methylidene group, unsaturated bonds or a phenylene group) into the .alpha. position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole increased 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 .ANG.. 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 .alpha.-methyl analog showed the highest potency with an IC50 [median inhibitory concentration] in the range of 10-8-10-9 M. Inhibition by these derivatives was highly selective for the TX synthetase, since other enzymes such as fatty acid cyclooxygenase and prostacyclin synthetase were not affected.