RESUMO
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 alpha position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole (15) 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 (47), 4-[3-(1-imidazolyl)-propyl]benzoic acid (50), and (E)-4-(1-imidazolylmethyl)cinnamic acid (54) and its alpha-methyl analogue (57) 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.
Assuntos
Imidazóis/farmacologia , Oxirredutases/antagonistas & inibidores , Tromboxano-A Sintase/antagonistas & inibidores , Animais , Coelhos , Ovinos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxirredutases/antagonistas & inibidores , Piridinas/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Animais , Ovinos , Relação Estrutura-AtividadeRESUMO
Novel prostaglandin analogues modified in the omega chain were prepared by the reaction of the vinyl aldehydes 1a--e with a variety of organometallic reagents as a key step of the syntheses. Compared with the natural prostaglandin F2 alpha in antinidatory effect, the analogues 4, 7, and 10 were 40 times more potent and the analogue 11 was 50--100 times more potent in the rat.