N- and 2-substituted N-(phenylsulfonyl)glycines as inhibitors of rat lens aldose reductase.

A variety of N-(phenylsulfonyl)-N-phenylglycines 5, N-(phenylsulfonyl)-2-phenylglycines 6, and N-(phenylsulfonyl)anthranilic acids 7 were prepared as analogues of the N-(phenylsulfonyl)glycine 1 aldose reductase inhibitors. In the rat lens assay, several derivatives of 5 display greater inhibitory activity than the corresponding glycines 1, suggesting that N-phenyl substitution enhances affinity for aldose reductase. Enzyme kinetic evaluations of the 4-benzoylamino analogues of 5 and 1 demonstrate that these compounds produce inhibition by the same mechanism. However, the significant differences in relative inhibitory potencies between compounds of series 5 and 1 may indicate that these compounds do not interact with the inhibitor binding site in precisely the same manner. Evaluation of the individual enantiomers of series 6 reveals that the S isomers are substantially more active than the corresponding R isomers. Also, with the exception of the naphthalene analogue 6n, the S stereoisomers of this series display greater inhibitory potencies than the glycines 1. The anthranilates 7 generally are less active than the glycines 1, demonstrating that direct incorporation of an aromatic ring in the glycine side chain may result in a decrease in affinity for aldose reductase.