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.
DeRuiter
J
J
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Alabama 36849.
Borne
R F
RF
Mayfield
C A
CA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007908:Lens, Crystalline / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology
D001557:Benzenesulfonates; D062367:ortho-Aminobenzoates; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D005998:Glycine