Rotationally restricted mimics of rigid molecules: nonspirocyclic hydantoin aldose reductase inhibitors |
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Authors: | J P Rizzi R C Schnur N J Hutson K G Kraus P R Kelbaugh |
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Institution: | Central Research Division, Pfizer Inc., Groton, Connecticut 06340. |
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Abstract: | 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. |
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