Quantitative structure activity relationship has been probed for spirosuccinimide-fused tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives acting as aldose reductase inhibitors. While the spirosuccinimide compounds contain a chiral center, the aldose reductase inhibition assay was performed with racemic mixtures in the published work. As the physicochemical descriptors of the QSAR analysis must be evaluated for a definite molecular structure, 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, closely reproducing the observed activity of optically pure enantiomers as well as racemic mixtures.Key Words : QSAR, Racemic descriptor, Aldose reductase inhibitor Modern drug discovery research relies on massive synthesis, assay and rational design of compounds to generate de novo lead molecular constructs.1,2 The lead compound is further optimized to enhance potency and deliverability. Quantitative structure activity relationship (QSAR) investigation aids lead optimization by analyzing the assay data in terms of molecular descriptors. While drug candidate molecules often contain chiral centers, the activity assay is rarely performed with optically pure enantiomers. In such cases, it is a challenging question which molecular structure to employ in evaluating the QSAR descriptors. We consider a simple arithmetic mean of enantiomeric descriptors as the QSAR basis and demonstrate its applicability to the QSAR analysis of spirosuccinimide aldose reductase inhibitors.Aldose reductase (AR) is the first enzyme of the sorbitol pathway in which it converts glucose to sorbitol.3 As high intracellular sorbitol accumulation causes chronic diabetic complications such as retinopathy, neuropathy, nephropathy, and cataracts, 4 inhibition of AR is an effective treatment for long-term diabetic malignity.5 Negoro et al. synthesized tetrahydropyrrolo[1,2-a]pyrazine derivatives and performed the assay.6 Although the spirosuccinimide cogeners contain the chiral center indicated by * in the figure of Table 1, the AR inhibition assay is performed with racemic mixtures.We obtain IC50 values of 30 spirosuccinimide compounds from the published data of Negoro et al. The AR inhibitory activity is defined as pIC50 = −log(IC50). The normalized pIC50 values of the training set are listed in Table 1. We utilize the Cerius 2 program package 7 and separately build the (S)-enantiomer and (R)-enantiomer molecular structures of the pyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone derivatives. For each enantiomer, thorough conformational search and energy minimization result in the optimized molecular geometry. The adopted basis Newton Raphson minimization method is used with the Merck Molecular Force Field. The optimized geometry is aligned to that of the most potent compound, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-...