Synthesis and biological activity of aldose reductase inhibitors with Michael acceptor substituents

Derivatives of alrestatin (15) and alconil (6-8) possessing Michael accepto r substituents were synthesized as aldose reductase inhibitors. The alresta tin derivatives demonstrated enhanced aldose reductase inhibitory activity. The most potent reversible inhibitor of the series (compound 3) was 15-fol d more active than alrestatin. Additionally, lipophilic analogues of alrest atin selectively inhibited rat lens aldose reductase versus rat kidney alde hyde reductase. Unlike alrestatin derivatives, alconil derivatives with sim ilar substituents did not demonstrate significant reversible or irreversibl e inhibition of aldose reductase. (C) Elsevier, Paris.