Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives.
The 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 carbon 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 (5a) had the highest potency (IC50 = 3 x 10(-9) M). The beta-substituted pyridine derivatives and 1-substituted imidazole derivatives which had the same side chain showed almost the same potency. The beta-substituted pyridine derivatives do not inhibit arachidonic acid cyclooxygenase or prostaglandin I2 synthetase, two other enzymes of the arachidonic cascade.
D000818:Animals; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012756:Sheep; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D011725:Pyridines; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase