Okushima H, Narimatsu A, Kobayashi M, Furuya R, Tsuda K, Kitada Y
J Med Chem. 1987 Jul;30(7):1157-61. doi: 10.1021/jm00390a007.
A series of [4-(substituted-amino)phenyl]pyridazinones and [4-(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30's (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 +/- 1.9 and 4.4 +/- 0.6 micrograms/kg, respectively, where that of amrinone was 471.9 +/- 94.1 micrograms/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.
合成了一系列[4-(取代氨基)苯基]哒嗪酮和[4-(取代甲基)氨基]苯基]哒嗪酮，并对其体外变力活性和体内心脏血液动力学效应进行了评估。最重要的是，6-[4-(4-吡啶基氨基)苯基]-4,5-二氢-3(2H)-哒嗪酮盐酸盐（4，MCI-154）和6-[4-(4-吡啶基氨基)苯基]-5-甲基-4,5-二氢-3(2H)-哒嗪酮盐酸盐（5）显示出极强的正性肌力活性以及血管舒张活性。关于dP/dtmax（心脏收缩力的指标），化合物4和5的ED30（使dP/dtmax增加30%的剂量）分别为8.5±1.9和4.4±0.6微克/千克，而氨力农的ED30为471.9±94.1微克/千克。给出了这些系列的构效关系，并讨论了一个合理的受体结合模型。
