Naito Y, Akahoshi F, Takeda S, Okada T, Kajii M, Nishimura H, Sugiura M, Fukaya C, Kagitani Y
Research Division, Green Cross Corporation, Osaka, Japan.
J Med Chem. 1996 Jul 19;39(15):3019-29. doi: 10.1021/jm9507993.
In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1-[(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1-[(methylamino)(thiocarbonyl)]-1H-tria zole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of > 2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)-induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.
为了基于新的作用机制开发新型抗哮喘药物，合成了一系列3-取代的5-氨基-1-[(甲氨基)(硫代羰基)]-1H-1,2,4-三唑衍生物，并在一个模型中进行评估，该模型通过在第0、2和5天静脉注射葡聚糖颗粒在气道中诱导嗜酸性粒细胞增多。在筛选了数百种衍生物后，我们最终确定了高效嗜酸性粒细胞增多抑制剂5-氨基-3-(4-氯苯基)-1-[(甲氨基)(硫代羰基)]-1H-三唑(23c，GCC-AP0341)，口服和腹腔注射时的ID50值分别为0.3和0.07 mg/kg。该化合物在腹腔注射剂量为1 mg/kg时，对蛔虫吸入诱导的超敏反应具有完全抑制作用，且毒性低，小鼠LD50值>2.0 g/kg。对其作用机制的深入研究表明，23c抑制白细胞介素-5(IL-5)诱导的嗜酸性粒细胞存活，但对白三烯D4(LTD4)或血小板活化因子(PAF)诱导的反应几乎没有影响。综上所述，这些结果表明23c是治疗慢性哮喘的新型候选药物。目前正在进行进一步的研究。
