Nakazawa M, Iizuka K, Ujiie A, Hiraku S, Ohki S
Kissei Pharmaceutical Co. Ltd., Central Research Laboratories, Nagano, Japan.
Yakugaku Zasshi. 1994 Dec;114(12):911-33. doi: 10.1248/yakushi1947.114.12_911.
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 beta-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 beta-(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 A for the inhibitory potency on TXA2 synthase. Among 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 x 10(-8) and 3 x 10(-9) M). 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-PGF1 alpha, 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.
血栓素（TX）A2合酶的高选择性抑制剂被视为治疗缺血性心脏病、血栓栓塞性疾病、脑循环障碍和哮喘的药物。1-取代咪唑和β-取代吡啶对TX A2合酶显示出高抑制活性。研究了咪唑和吡啶衍生物作为TX A2合酶抑制剂的构效关系。发现将各种取代基引入1-(7-羧基庚基)咪唑和β-(7-羧基庚基)吡啶的含羧基侧链可提高抑制活性。对于TX A2合酶的抑制活性，带有亚苯基的侧链长度在8.5至10埃范围内最为适宜。在所测试的咪唑和吡啶衍生物中，(E)-4-(1-咪唑基甲基)肉桂酸（44）和(E)-3-[4-(3-吡啶基甲基)苯基]-2-甲基丙烯酸（56）显示出最高活性（IC50 = 1.1×10⁻⁸和3×10⁻⁹ M）。这些衍生物的抑制作用对TX A2合酶具有高度选择性，因为参与花生四烯酸级联反应的其他酶，如脂肪酸环氧化酶、5-脂氧合酶、前列环素（PGI2）合酶和PGE2异构酶均未受影响。基于对这两种化合物（44和56）进行的药理、物理化学和毒理学研究结果，(E)-4-(1-咪唑基甲基)肉桂酸（44；OKY-046，奥扎格雷）被选为TX A2合酶高选择性抑制剂的最佳化合物。奥扎格雷的药理特性如下。奥扎格雷对TX A2合酶的抑制作用对人和兔的酶比其他物种的酶更有效。奥扎格雷可能通过抑制TX A2合酶导致PG内过氧化物积累，从而在各种分离的细胞和组织中增加6-酮-PGF1α（PGI2的一种稳定代谢产物）。在各种实验动物中也观察到奥扎格雷使PGI2生成增加。我们得到的提示是，通过减少TX A2生成和增加PGI2生成，奥扎格雷可抑制将自体血注入蛛网膜下腔的犬的基底动脉痉挛和局部脑血流量减少，并抑制脑缺血治疗动物的运动功能和局部脑血流量下降以及梗死区域的形成。还提示奥扎格雷可抑制豚鼠中白三烯、血小板活化因子和抗原诱导的支气管收缩，并通过两种机制抑制多种动物中各种刺激诱导的气道高反应性。还描述了ADME、毒理学和临床研究的总结结果。
