Rizzi J P, Schnur R C, Hutson N J, Kraus K G, Kelbaugh P R
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
J Med Chem. 1989 Jun;32(6):1208-13. doi: 10.1021/jm00126a011.
Sorbinil (1), a spirocyclic hydantoin, is a potent inhibitor of the enzyme aldose reductase. Simulation of the rigid spirocyclic ring orientation found in sorbinil was achieved with nonspirocyclic 5-[5'-chloro-2'-(alkylsulfonyl)-phenyl]hydantoins and 5-[5'-chloro-2'-[(N-alkylamino)sulfonyl]phenyl]hydantoins. The 2'-substituent (SO2R) was sufficiently large to hinder rotation of the hydantoin ring, forcing an orientation similar to that of a spirocyclic hydantoin. Calculated conformational preference, X-ray data, and inhibitory IC50 values for these nonspirocyclic 2'-substituted (SO2R) phenylhydantoins are in accord with what is expected for spirocyclic hydantoins and comparable to those of sorbinil.
索比尼尔（1），一种螺环乙内酰脲，是醛糖还原酶的强效抑制剂。通过非螺环5-[5'-氯-2'-(烷基磺酰基)-苯基]乙内酰脲和5-[5'-氯-2'-[(N-烷基氨基)磺酰基]苯基]乙内酰脲实现了对索比尼尔中发现的刚性螺环取向的模拟。2'-取代基（SO₂R）足够大，可阻碍乙内酰脲环的旋转，迫使形成类似于螺环乙内酰脲的取向。这些非螺环2'-取代（SO₂R）苯基乙内酰脲的计算构象偏好、X射线数据和抑制IC₅₀值与螺环乙内酰脲的预期相符，且与索比尼尔的相当。
