Quantitative structure and aldose reductase inhibitory activity relationship of 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone derivatives.
We investigate the quantitative structure-activity relationship of spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives acting as aldose reductase inhibitors, which contain a chiral center. The published assay data of 30 training compounds are not for optically pure enantiomer preparations but for racemic mixtures. As the physicochemical descriptors for the QSAR analysis must be evaluated for either (R)-enantiomer or (S)-enantiomer, we devise a new 'racemic' descriptor as the arithmetic mean of the (R)-enantiomer descriptor and the (S)-enantiomer descriptor. The resultant QSAR model derived from the racemic descriptors outperforms the original QSAR models. The racemic QSAR model shows that the hydrophobic character of the benzyl moiety is the major contributing factor to the aldose reductase inhibitory activity and the polar surface area descriptors modulate the inhibitory activity.
Ko
Kwangseok
K
Department of Chemistry, Hanyang University, Seoul 133-792, Korea.
Won
Youngdo
Y
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*
C502253:1,2,3,4-tetrahydropyrrolo(1,2-a)pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013141:Spiro Compounds; D000449:Aldehyde Reductase