Rooney C S, Randall W C, Streeter K B, Ziegler C, Cragoe E J, Schwam H, Michelson S R, Williams H W, Eichler E, Duggan D E, Ulm E H, Noll R M
J Med Chem. 1983 May;26(5):700-14. doi: 10.1021/jm00359a015.
An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.
已经制备了一系列新型的4-取代-3-羟基-1H-吡咯-2,5-二酮衍生物，并作为乙醇酸氧化酶（GAO）的抑制剂进行了研究。一般来说，具有大的亲脂性4-取代基的化合物是猪肝脏GAO在体外的有效竞争性抑制剂。氮或3-羟基取代基的甲基化显著降低了活性，表明1H-吡咯-2,5-二酮核上需要两个酸性官能团。在大鼠肝脏灌注研究中，使用三种代表性化合物，观察到[1-14C]乙醇酸向[14C]草酸盐转化的浓度依赖性抑制。对喂食乙二醇的大鼠长期口服4-(4'-溴[1,1'-联苯]-4-基)衍生物（83），结果显示在58天的时间里尿草酸盐水平显著降低。
