Highly Selective Inhibitors of Thromboxane Synthetase. 2. Pyridine Derivatives

Article abstract of DOI:10.1021/jm00142a006

The enzyme thromboxane (TX) synthetase is inhibited by pyridine.The β-substituted pyridine derivatives showed higher inhibitory potency than γ-substituted ones having the side chain.Among the β-substituted derivatives containing the ω-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*10^-9 M).The β-substituted pyridine derivatives and 1-substituted imidazole derivatives which had the same side chain showed almost the same potency.The β-substituted pyridine derivatives do not inhibit arachidonic acid cyclooxygenase or prostaglandin I₂ synthetase, two other enzymes of the arachidonic cascade.