DeRuiter J, Swearingen B E, Wandrekar V, Mayfield C A
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Alabama 36849.
J Med Chem. 1989 May;32(5):1033-8. doi: 10.1021/jm00125a017.
A number of N-benzoylglycines (6), N-acetyl-N-phenylglycines (7), N-benzoyl-N-phenylglycines (8), and tricyclic N-acetic acids (9-12) were synthesized as analogues of the N-acylglycine-containing aldose reductase inhibitors alrestatin and 2-oxoquinoline-1-acetic acid. Derivatives of 6, which represent ring-simplified analogues of alrestatin, are very weak inhibitors of aldose reductase obtained from rat lens, producing 50% inhibition only at concentrations exceeding 100 microM. Compounds of series 7 were designed as ring-opened analogues of the 2-oxoquinolines. While these derivatives are more potent than compounds of series 6 (IC50S of 6-80 microM), they are less active than the corresponding 2-oxoquinolines. Analogues of series 8 were designed as hybrid structures of both alrestatin and the 2-oxoquinoline-1-acetic acids. These compounds are substantially more potent than compounds of series 6 and 7 and display inhibitory activities comparable to or greater than alrestatin or the 2-oxoquinolines (IC50S of 0.1-10 microM). Of the rigid analogues of 8, the most potent derivative is benzoxindole (12) with an IC50 of 0.67 microM, suggesting that fusion of the two aromatic rings of 8 in a coplanar conformation may optimize affinity for aldose reductase in this series.
合成了多种N - 苯甲酰甘氨酸（6）、N - 乙酰 - N - 苯基甘氨酸（7）、N - 苯甲酰 - N - 苯基甘氨酸（8）和三环N - 乙酸（9 - 12），作为含N - 酰基甘氨酸的醛糖还原酶抑制剂阿雷司他汀和2 - 氧代喹啉 - 1 - 乙酸的类似物。6的衍生物是阿雷司他汀的环简化类似物，对从大鼠晶状体中获得的醛糖还原酶的抑制作用非常弱，仅在浓度超过100 microM时才产生50%的抑制作用。7系列化合物被设计为2 - 氧代喹啉的开环类似物。虽然这些衍生物比6系列化合物更有效（IC50为6 - 80 microM），但它们的活性低于相应的2 - 氧代喹啉。8系列类似物被设计为阿雷司他汀和2 - 氧代喹啉 - 1 - 乙酸的杂化结构。这些化合物比6系列和7系列化合物的效力要强得多，并且显示出与阿雷司他汀或2 - 氧代喹啉相当或更强的抑制活性（IC50为0.1 - 10 microM）。在8的刚性类似物中，最有效的衍生物是苯并吲哚（12），IC50为0.67 microM，这表明8的两个芳环以共平面构象融合可能会优化该系列对醛糖还原酶的亲和力。
