Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives

Abstract

The human enzyme thromboxane (TX) synthetase is inhibited by pyridine. The .beta.-substituted pyridine derivatives showed higher inhibitory potency than the .gamma.-substituted ones having the same side chain. Among the .beta.-substituted derivatives containing the .omega.-carboxyalkyl group, the compounds with 6-8 C atoms in the side chain were especially effective. The derivatives holding the phenylene group in the side chain exhibited much higher inhibitory activity than those of the alkylene type. Among them, (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methylacrylic acid hydrochloride had the highest potency (IC50 [median inhibitory concentration] = 3 .times. 10-9 M). The .beta.-substituted pyridine derivatives and 1-substituted imidazole derivatives with the same side chain showed almost the same potency. The .beta.-substituted pyridine derivatives do not inhibit arachidonic acid cyclooxygenase or prostaglandin I2 synthetase, 2 other enzymes of the arachidonic cascade.