Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors

Christopher A. Lipinski ,* Charles E . Aldinger , Thomas A. Beyer , Jon Bordner , Douglas F . Burdi, Donald L . Bussolotti, Philip B . Inakeep , and Todd W . Siegel Central Research Diuision, Pfizer Inc., Groton, Connecticut 06340. Received April 29, 1991 The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin l to a bioisosteric analysis end replacement of the hydantoin by a spiro hydroay acetic acid moiety as in 40. ring ed These hyth acids, compered to bydantoins, showed a similar potency increase on cluomm 2-methyl substitution, e similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioseleM )vity. In this aeries