[Imidazolidine/thiazolidine-acetate aldose reductase inhibitors].
We studied a new family of aldose-reductase inhibitors with an imidazolidine arylmethylene and thiazolidine-acetate structure susceptible to prevent ocular, renal and vascular complications of insulin-dependent diabetes mellitus. We examined the role of the enzyme in the pathological processes involved and reviewed knowledge of known aldose reductase inhibitors leading to the development of the basic structure modulated to have insight into the different elements of the structure-quantitative activity relationship. Potential inhibitors are synthesized by condensation of heterocyclic rings and aldehyde aromatic rings. Their identity and structure were established by magnetic resonance spectroscopy (MRS) based on proton-carbon couplage constants and the homonuclear NOE effect. The structure-activity correlations were analyzed on the basis of the IC50 using a structural model and a physicAL model which showed the importance of the sulfur atom in the heterocyclic ring due to its important lipophilic contribution. Finally, a molecular modeling approach led to a provisional descriptive model of the inhibitor-enzyme interaction.
Fresneau
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Laboratoire de Chimie Thérapeutique, Groupe de Pharmacochimie Moléculaire, Faculté de Pharmacie, F38700 La Tronche.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D003930:Diabetic Retinopathy / Q000517:prevention & control*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D013844:Thiazoles; D000449:Aldehyde Reductase