Quantitative structure-activity relationship of spirosuccinimide type aldose reductase inhibitors diminishing...

Racemate physicochemical descriptors are employed to probe the quantitative structure-activity relationship of spirosuccinimide type aldose reductase inhibitors and the in vivo inhibitory activity of sorbitol accumulation. The in vivo activity data include the percent inhibition and ED50 assay results on the literature. The derived QSAR equations show that the hydrophobic character of aldose reductase inhibitor is the major contributing factor to enhance in vivo activity. As the hydrophobicity of compounds is related to both the membrane permeability and the binding affinity to the aldose reductase, its contribution to the pharmacokinetic behavior is further scrutinized by evaluating pKa and the Caco-2 cell permeability. The high correlation between ED50 and the Caco-2 cell permeability of in vitro active compounds indicates that the membrane permeability is essential for in vivo efficacy.