Iizuka K, Akahane K, Momose D, Nakazawa M, Tanouchi T, Kawamura M, Ohyama I, Kajiwara I, Iguchi Y, Okada T, Taniguchi K, Miyamoto T, Hayashi M
J Med Chem. 1981 Oct;24(10):1139-48. doi: 10.1021/jm00142a005.
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.
研究了咪唑衍生物作为血栓素（TX）合成酶抑制剂的构效关系。在1-(7-羧基庚基)咪唑（15）的含羧基侧链的α位或其他位置引入各种取代基（如一个或两个甲基、一个卤原子、一个亚甲基、不饱和键或一个亚苯基），发现可提高抑制效力。带有亚苯基的侧链长度在8.5 - 9.0 Å范围内对TX合成酶的抑制效力最佳。在所测试的咪唑衍生物中，1-(7-羧基-7-甲基-2-辛炔基)咪唑（47）、4-[3-(1-咪唑基)-丙基]苯甲酸（50）、(E)-4-(1-咪唑基亚甲基)肉桂酸（54）及其α-甲基类似物（57）显示出最高的效力，IC50在10^(-8)至10^(-9) M范围内。这些衍生物的抑制作用对TX合成酶具有高度选择性，因为其他酶如脂肪酸环氧化酶和前列环素合成酶不受影响。
