Ao S, Shingu Y, Kikuchi C, Takano Y, Nomura K, Fujiwara T, Ohkubo Y, Notsu Y, Yamaguchi I
Laboratory of Biological Science, Fujisawa Pharmaceutical Co., Ltd, Ibaraki, Japan.
Metabolism. 1991 Jan;40(1):77-87. doi: 10.1016/0026-0495(91)90196-4.
FR74366 (FK366) ([3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-1-yl] acetic acid) is a chemically novel aldose reductase (AR) inhibitor. It exhibited a highly potent, reversible, and mixed type inhibition of partially purified AR from the rat sciatic nerve (IC50 = 3.6 nmol/L) and rat lens (IC50 = 4.4 nmol/L). FR74366 inhibited sorbitol accumulation in the isolated human erythrocyte (IC50 = 1.6 mumol/L), rat lens (IC50 = 39 mumol/L), and rat sciatic nerve (IC50 = 17 mumol/L) incubated with high glucose concentrations. The oral administration of FR74366 to streptozotocin (STZ)-induced diabetic rats for 2 weeks decreased sorbitol levels (ED50 = 3.7 mg/kg for sciatic nerve, 23 mg/kg for lens, 52 mg/kg for retina, and 62 mg/kg for renal cortex). Administration of FR74366 to diabetic rats for 17 weeks delayed cataract formation and admixture of 0.028% FR74366 in the diet completely inhibited the cataract formation. Moreover, the recovery of reduced motor nerve conduction velocity by FR74366 in diabetic rats was demonstrated in prevention and reversal experiments. This recovery effect correlated well with reduction of accumulated sorbitol and fructose levels and normalization of decreased myoinositol levels. The duration and tissue specificity of inhibitory effects of FR74366 on sorbitol accumulation also correlated well with the levels of FR74366 in various tissues of diabetic rats. These data indicate that both decreases in tissue sorbitol levels and improvement of functional defects reflect FR74366 levels in tissue rather than plasma in diabetic rats. These results, taken together, suggest that FR74366, which is currently undergoing clinical trials in Japan and the United States, will be a useful therapeutic agent for diabetic complications.
FR74366（FK366）（[3 - （4 - 溴 - 2 - 氟苄基） - 7 - 氯 - 2,4 - 二氧代 - 1,2,3,4 - 四氢喹唑啉 - 1 - 基]乙酸）是一种化学结构新颖的醛糖还原酶（AR）抑制剂。它对大鼠坐骨神经部分纯化的AR（IC50 = 3.6 nmol/L）和大鼠晶状体（IC50 = 4.4 nmol/L）表现出高效、可逆且混合型抑制作用。FR74366抑制在高糖浓度下孵育的分离人红细胞（IC50 = 1.6 μmol/L）、大鼠晶状体（IC50 = 39 μmol/L）和大鼠坐骨神经（IC50 = 17 μmol/L）中山梨醇的积累。给链脲佐菌素（STZ）诱导的糖尿病大鼠口服FR74366两周可降低山梨醇水平（坐骨神经的ED50 = 3.7 mg/kg，晶状体的ED50 = 23 mg/kg，视网膜的ED50 = 52 mg/kg，肾皮质的ED50 = 62 mg/kg）。给糖尿病大鼠服用FR74366 17周可延缓白内障形成，且在饮食中添加0.028%的FR74366可完全抑制白内障形成。此外，在预防和逆转实验中证实了FR74366可使糖尿病大鼠降低的运动神经传导速度恢复。这种恢复效果与积累的山梨醇和果糖水平降低以及降低的肌醇水平恢复正常密切相关。FR74366对山梨醇积累的抑制作用的持续时间和组织特异性也与糖尿病大鼠各组织中FR74366的水平密切相关。这些数据表明，组织中山梨醇水平的降低和功能缺陷的改善反映的是糖尿病大鼠组织中而非血浆中的FR74366水平。综上所述，这些结果表明，目前正在日本和美国进行临床试验的FR74366将是一种治疗糖尿病并发症的有效药物。
