Rotationally restricted mimics of rigid molecules: nonspirocyclic hydantoin aldose reductase inhibitors.
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.
Rizzi
J P
JP
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
Schnur
R C
RC
Hutson
N J
NJ
Kraus
K G
KG
Kelbaugh
P R
PR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008968:Molecular Conformation; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D013450:Sulfones
D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D013449:Sulfonamides; D013450:Sulfones; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil