Kato K, Nakayama K, Mizota M, Miwa I, Okuda J
Department of Pharmacology, Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan.
Chem Pharm Bull (Tokyo). 1991 Jun;39(6):1540-5. doi: 10.1248/cpb.39.1540.
Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.
新型醛糖还原酶（AR）抑制剂M16209（1-(3-溴苯并[b]呋喃-2-基磺酰基)乙内酰脲）和M16287（1-(3-氯苯并[b]呋喃-2-基磺酰基)乙内酰脲）的性质和功效在体外和体内进行了研究，并与已知的AR抑制剂ONO-2235和索比尼尔进行了比较。这四种化合物抑制了来自不同来源的部分纯化醛糖还原酶，M16209和M16287的效力总体上与ONO-2235相似，且大于索比尼尔。这四种AR抑制剂的IC50值基本上不取决于所使用的底物。对部分纯化的牛晶状体（BLAR）抑制作用的动力学研究表明，M16209、M16287和索比尼尔对甘油醛无竞争性，对烟酰胺腺嘌呤二核苷酸磷酸（NADPH）无竞争性，而ONO-2235对甘油醛和NADPH均无竞争性。随着酶纯化的进行，醛糖还原酶对这四种抑制剂的敏感性降低，尽管与二硫苏糖醇孵育可部分逆转抑制敏感性。此外，这四种化合物对所测试的碳水化合物和谷胱甘肽代谢的那些酶有轻微影响。M16209和M16287预防分离大鼠组织中山梨醇积累的效力与ONO-2235和索比尼尔相当。M16209和M16287在预防半乳糖血症性白内障和改善糖尿病神经病变方面几乎具有相同的效力，而ONO-2235仅对神经病变有效，索比尼尔对半乳糖血症性白内障和糖尿病神经病变有效，但效力不同。这些结果表明，M16209和M16287是有效的醛糖还原酶抑制剂，可用于治疗糖尿病并发症。
