作者:Norimasa Kanamitsu、Takashi Osaki、Yutaka Itsuji、Masakazu Yoshimura、Hisashi Tsujimoto、Manabu Soga
DOI:10.1248/cpb.55.1682
日期:——
We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(−), 5(−), 27(−), and 47(−) [JM-1232(−)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(−) [JM-1232(−)] is being considered as the most potential candidate for clinical trials in humans.
我们开发了以异吲哚啉-1-酮为骨架的新型静脉注射镇静催眠化合物,重点关注其水溶性和体内安全性。我们合成了约 170 种衍生物,并通过给小鼠静脉注射这些化合物评估了它们的催眠效果。一系列 2-苯基-3-[2-(4-甲基-1-哌嗪基)-2-氧代乙基]异吲哚啉-1-酮类似物 3(-)、5(-)、27(-)和 47(-) [JM-1232(-)]显示出强大的镇静催眠活性,且具有良好的水溶性和较宽的安全范围。这 4 种化合物对小鼠的催眠剂量(HD50s)分别为 2.35、1.90、2.17 和 3.12 mg/kg,致死剂量(LD50s)分别为 88.67、64.69、>120 和>120 mg/kg。治疗指数(LD50/HD50)分别为 37.73、34.05、>55.30 和 >38.46。在这些化合物中,47(-)[JM-1232(-)] 被认为是最有可能进行人体临床试验的候选化合物。