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Aldose Reductase (AR, ALR2)
Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications.
2. Main Results and Future Perspectives
several promising series of aldose reductase inhibitors/antioxidants as summarized in Figure 2.
Figure 2. Carboxymethyl pharmacophore regioisomerization in AR inhibitory activity optimization starting from the non-active hexahydropyridoindole scaffold 1a
Starting from the efficient hexahydropyridoindole antioxidant stobadine (1a), two series of hexahydro- and tetrahydropyridoindoles carboxymethylated in position 8 were synthesized and characterized as AR inhibitors with negligible (e.g. compound 1b) or mild (e.g. compounds 2b,c) efficacy and selectivity yet with significant antioxidant (AO) effect as an additional biological activity. The hexahydropyridoindole scaffold was excluded from further drug design since the marked antioxidant activity of the hexahydropyridoindoles was combined with only minor AR inhibition (e.g. compound 1b) which was explained by space distortion of the hexahydropyridoindole structure not fitting properly the AR binding pocket. Tetrahydropyridoindole congeners with a planar tricyclic moiety appeared more promising route in designing efficient ARIs. Notably, elimination of the basicity center at N2 position, which prevented zwitterions formation, significantly improved AR inhibition as shown in the case of compound 2e.
Shifting the carboxymethyl pharmacophore from position 8 to position 2, yielded derivatives with markedly decreased inhibition efficacy, as exemplified by compound 2g, therefore this route of drug designing was not further followed.
Structure optimization of the tetrahydropyridoindole scaffold by transferring the carboxymethyl pharmacophore from position 8 to position 5, yielded derivatives with markedly enhanced inhibition efficacy and selectivity, yet with abolished AO activity (e.g. compounds 3a,d,f). In this series, the AR inhibition efficacy markedly increased with decreasing basicity of N2 nitrogen as documented by compound 3f.
Thioxotriazine structural alternatives yielded highly efficient AR inhibitors (e.g. compound 5a) with high selectivity and reasonable AO activity. In further structure optimization efforts, isosteric replacement of sulfur in compound 5a with oxygen provided compound 7a with increased AR inhibition efficacy and markedly improved selectivity, yet with diminished AO activity.
Interestingly, the structural features of the most efficient ARIs resulting from the above optimization procedure, namely compounds 2c, 3f, 5a and 7a (IC50(ALR2) = 18 000; 13; 97; 42 nM, resp.) still match the strict criteria of the „rule of three“, which points to their excellent “leadlikeness” with prospects of further structure optimizations.
This entry is adapted from 10.3390/molecules26102867
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