Heilman W P, Heilman R D, Scozzie J A, Wayner R J, Gullo J M, Ariyan Z S
J Med Chem. 1979 Jun;22(6):671-7. doi: 10.1021/jm00192a012.
In an effort to develop antihypertensive agents with peripheral vasodilator activity, a series of 40 novel 3-hydrazino-5-phenyl-1,2,4-triazines (II) were synthesized and evaluated in the spontaneously hypertensive rat assay (SHR assay). Based on the performance of the structurally related standard, hydralazine (I), 15 triazines were active. Thirteen of these hypotensive triazines possessed LD50 values in the mouse greater than I (LD50 = 100 mg/kg); only one active triazine had an LD50 value greater than 300 mg/kg (11d). Four asymmetric triazines had moderate antihypertensive activity and LD50 values greater than 300 mg/kg (6b, 7c, 8f, and 9g). Based on the relationship between toxicity and antihypertensive activity, three triazines (8f, 9g, and 11d) were chosen for dose-responses studies in the SHR assay. None were as efficacious as I, but all three were less toxic, resulting in similar therapeutic indices relative to I.
为了开发具有外周血管舒张活性的抗高血压药物，合成了一系列40种新型的3-肼基-5-苯基-1,2,4-三嗪（II），并在自发性高血压大鼠试验（SHR试验）中进行了评估。基于结构相关标准品肼屈嗪（I）的表现，有15种三嗪具有活性。其中13种降压三嗪在小鼠中的半数致死量（LD50）值大于I（LD50 = 100 mg/kg）；只有一种活性三嗪的LD50值大于300 mg/kg（11d）。四种不对称三嗪具有中等抗高血压活性，且LD50值大于300 mg/kg（6b、7c、8f和9g）。基于毒性与抗高血压活性之间的关系，选择了三种三嗪（8f、9g和11d）在SHR试验中进行剂量反应研究。没有一种与I一样有效，但这三种毒性均较小，相对于I而言具有相似的治疗指数。
