Structure optimization of tetrahydropyridoindole-based aldose reductase inhibitors improved their efficacy and selectivity

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

“…Transferring the carboxymethyl pharmacophore from position 8 to position 5, yielded derivatives (series 3 ) with markedly enhanced aldose reductase inhibition efficacy and selectivity ( Table 2 ) [ 71 ]. Mild inhibition characterized by IC 50 in micromolar range was recorded for compound 3a with the isopropyl substituent in position 2.…”

“…As shown in the fitted molecular surface ( Figure 4 B), lidorestat induced a narrower access to the cavity, keeping amino acids Trp219 and Leu300 closer in comparison with the complex of 3f. The amino group of Gln49 (colored in green in Figure 4 B) is perpendicular to the surface of the protein in the complex with lidorestat ( Figure 4 B left), while for 3f this group is parallel to the surface ( Figure 4 B right) [ 71 ].…”

“…This effect may be obviously assigned to the higher affinity to ALR1 of compound 3e bearing the carboxyl group, since the alterations of the 8-metoxy vs. 8-carboxyl substituents did not affect ALR2 inhibition. In silico study revealed a strong interaction of compound 3f with Phe122, Trp219, Leu300, and Tyr309 from the “specificity pocket”, set of residues in ALR2 which are not conserved in ALR1 [ 71 ]. The highest selectivity was recorded for compound 3d with the corresponding selectivity factor exceeding 1000.…”

“…Zopolrestat used as reference gave for AKR1B1 the IC 50 value of 25 nM, while for AKR1B10 it was inactive. According to the docking study, selectivity of compound 3f towards AKR1B10 is related to the fact that in Cys298 is replaced by hydroxylated cysteine Cso299, which creates H-bond with the acetate group of compound 3f and keeps it too far from NADP + to form the hydrophobic interaction with nicotinamide ring [ 71 ].…”

Ligand-Based Drug Design of Novel Aldose Reductase Inhibitors

“…Besides, the hydrophobic interaction between methyl of acetyl group and nicotinamide ring, which is typical for all inhibitors of this type, we can observe an increasing number of H-bonds when inspecting inhibitors from weak to strong (alrestatin, epalrestat, tolrestat, zenarestat, cemtirestat, zopolrestat, lidorestat; corresponding pdb structures 1az1, 4jir, 2fzd, 1iei, 4qx4, 2fz8, 1z3n). The tricyclic framework, combining the skeleton rigidity with the proper placement of the functional acetyl group, was found to be advantageous for exact setting of new substituents which could ensure other properties, for example, high selectivity toward aldehyde reductase [13].…”