Sarges R, Peterson M J
Metabolism. 1986 Apr;35(4 Suppl 1):101-4. doi: 10.1016/0026-0495(86)90196-4.
A decade ago, we discovered that spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. This important discovery resulted from a systematic screening effort for in vitro activity against aldose reductase isolated from bovine lens and subsequent testing of active compounds for in vivo activity in a streptozotocin-diabetic rat model, measuring inhibition of sorbitol formation in sciatic nerve. In this in vivo model, spirohydantoins were clearly more potent than all known carboxylic acid-type aldose reductase inhibitors. Structure-activity studies in the spirohydantoin class demonstrated that potent in vitro and in vivo activity were obtained when the spiro junction was adjacent to an aromatic ring and when this junction was part of a 5- or 6-membered ring system fused to the aromatic ring. Excellent in vitro and in vivo activity was achieved in 6-halogenated chromane derivatives with the spirohydantoin group attached in the 4-position. In this series, biologic activity is highly stereospecific and associated with the S configuration. Sorbinil, the S isomer of the 6-fluoro derivative in this series, is one such example: it is 30 times more potent than its R isomer in vitro (IC50 0.15 v 4.4 mumol/L) and 100 times more potent in vivo (ED50 0.25 mg/kg po v 25 mg/kg po).
十年前，我们发现螺环乙内酰脲是一类新型的醛糖还原酶抑制剂，其特点是具有很强的体内活性。这一重要发现源于对从牛晶状体中分离出的醛糖还原酶进行体外活性的系统筛选，以及随后在链脲佐菌素诱导的糖尿病大鼠模型中对活性化合物进行体内活性测试，测量坐骨神经中山梨醇形成的抑制情况。在这个体内模型中，螺环乙内酰脲明显比所有已知的羧酸型醛糖还原酶抑制剂更有效。螺环乙内酰脲类的构效关系研究表明，当螺环连接点与芳环相邻且该连接点是与芳环稠合的五元或六元环系统的一部分时，可获得较强的体外和体内活性。在4位连接有螺环乙内酰脲基团的6-卤代色满衍生物中实现了优异的体外和体内活性。在这个系列中，生物活性具有高度的立体特异性，且与S构型相关。该系列中6-氟衍生物的S异构体索比尼尔就是一个例子：它在体外的活性比其R异构体高30倍（IC50为0.15对4.4 μmol/L），在体内高100倍（ED50为0.25 mg/kg口服对25 mg/kg口服）。
