Mylari B L, Beyer T A, Siegel T W
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
J Med Chem. 1991 Mar;34(3):1011-8. doi: 10.1021/jm00107a020.
Ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (1, EBPC) is a potent and specific inhibitor of aldose reductase. It was greater than 4000X more potent in its inhibition of rat lens aldose reductase than the closely related rat or pig kidney aldehyde reductase, thus making it the most selective inhibitor of a NADPH-dependent carbonyl reductase identified to date. In agreement with this observation, it was found to be a highly potent inhibitor of aldose reductase from rat sciatic nerve with greater than 98% inhibition at 1 microM, but it was practically devoid of activity against aldehyde reductases from rat liver and brain. Inhibition of aldose reductase was mixed type for glyceraldehyde (Ki = 8.0 x 10(-8) M) and noncompetitive for NADPH (Ki = 1.70 x 10(-8) M). Its potential as an in vitro tool to quantitate monomeric aldo/keto reductase activities in crude tissue extracts is presented. Structure-activity relationships emerging from synthetic modifications of EBPC are discussed. Several modifications were found to be active in vitro against aldose reductase from human placenta and in vivo in a rat model of diabetic complications, but none was more potent than EBPC.
1-苄基-3-羟基-2(5H)-氧代吡咯-4-羧酸乙酯（1，EBPC）是一种强效且特异性的醛糖还原酶抑制剂。其对大鼠晶状体醛糖还原酶的抑制作用比密切相关的大鼠或猪肾醛糖还原酶强4000多倍，因此是迄今为止已鉴定出的对NADPH依赖性羰基还原酶最具选择性的抑制剂。与该观察结果一致，发现它是大鼠坐骨神经醛糖还原酶的高效抑制剂，在1 microM时抑制率大于98%，但对大鼠肝脏和脑的醛糖还原酶几乎没有活性。对甘油醛的醛糖还原酶抑制作用为混合型（Ki = 8.0 x 10(-8) M），对NADPH为非竞争性（Ki = 1.70 x 10(-8) M）。介绍了其作为体外定量粗组织提取物中单体醛糖/酮糖还原酶活性工具的潜力。讨论了EBPC合成修饰产生的构效关系。发现几种修饰在体外对人胎盘醛糖还原酶有活性，在糖尿病并发症大鼠模型中在体内也有活性，但没有一种比EBPC更有效。
