Novel inhibitors of rat lens aldose reductase: N-[[(substituted amino)phenyl]sulfonyl]glycines.

Abstract

A number of N-[[(substituted amino)phenyl]sulfonyl]glycines 3a-n were synthesized as analogues of the simple (phenylsulfonyl)glycines 1a-c with increased lipophilic character and therefore greater aldose reductase inhibitory potential. The 2-benzoylamino derivative 3c was found to be less potent than the corresponding amine 1c as an inhibitor of rat lens aldose reductase, but both the 3- and 4-benzoylamino analogues, 3b and 3a, are substantially more potent than their amines 1b and 1a; compound 3a is the most effective inhibitor of this series, with an IC50 of 0.41 microM. The 4-benzoylamino derivative 3a is also significantly more active than the 4-acetylamino analogue 3d and the 4-benzylamino (3e) and 4-dimethylamino (3f) derivatives, suggesting that both the additional carbonyl moiety and aromatic ring present in this compound may bind to complementary sites present on the enzyme. Furthermore, structure-activity studies reveal that increasing the number of atoms between the carbonyl and aromatic moieties of 3a results in a decrease in inhibitory activity. Kinetic studies demonstrate that 3a, like other known inhibitors of aldose reductase, functions as an uncompetitive inhibitor with respect to the substrate and therefore may interact at the proposed common inhibitor binding site of this enzyme.