Research and Development of Ozagrel, a Highly Selective Inhibitor of TXA<SUB>2</SUB> Synthase

Highly selective inhibitors of thromboxane (TX) A₂ synthase were noted as a therapeutic agent for ischemic heart diseases, thromboembolic disorders, cerebral circulatory disorders, and asthma. The 1-substituted imidazoles and β-substituted pyridines showed high inhibitory potency on TXA₂ synthase. The structure-activity relationships of the imidazole and pyridine derivatives as inhibitors of TXA₂ synthase were investigated. Introduction of various substituents into the carboxy-bearing side chain of 1-(7-carboxyheptyl) imidazole and β-(7-carboxyheptyl) pyridine was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum in the region of 8.5 to 10 Å for the inhibitory potency on TXA₂ synthase. Amoung the tested imidazole and pyridine derivatives, (E)-4-(1-imidazolylmethyl) cinnamic acid (44) and (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylic acid (56) showed the highest potency (IC₅₀=1.1×10^-8 and 3×10^-9M). The inhibition by these derivatives was highly selective for TXA₂ synthase, since other enzymes which are involved in the arachidonic acid cascade, such as fatty acid cyclooxygenase, 5-lipoxygenase, prostacyclin (PGI₂) synthase, and PGE₂ isomerase were not affected. On the basis of the results obtained from the pharmacological, physicochemical and toxicological studies on the two compounds (44 and 56), (E)-4-(1-imidazolylmethyl) cinnamic acid (44 ; OKY-046, ozagrel) was selected as the best compound of highly selective inhibitors of TXA₂ synthase. The pharmacological properties of ozagrel are as follows. The inhibition of TXA₂ synthase by ozagrel was more effective on human and rabbit enzymes than those of other species. Ozagrel increased 6-keto-PGF_1a, one of stable metabolites of PGI₂, in various isolated cells and tissues perhaps via accumulated PG endoperoxides resulted by the inhibition of TXA₂ synthase. Such an increase in PGI₂ production by ozagrel was also observed in various experimental animals. We obtained the suggestion that, by the reduction of TXA₂ production and increment of PGI₂ production, ozagrel inhibits the spasms of basilar artery and the decreases in regional cerebral blood flow in dogs which received autologous blood into cisterna magna, and inhibits the decreases in motor function and regional cerebral blood flow, and the formation of infarcted area in the animals of cerebral ischemic treatment. It was also suggested that ozagrel inhibits leukotriene-, platelet-activating factor-, and antigen-induced bronchoconstriction in guinea-pigs and inhibits the induction of airway hyperresponsiveness by various stimuli in several species of animals by both mechanisms. The summarized results of ADME, toxicological, and clinical studies were also described.