New highly effective and selective aldose reductase inhibitor DPI-1 for the treatment of diabetic complications
Jana Ballekova 1
Marta Soltesova Prnova 1
Milan Štefek 1
Magdaléna Májeková 1
1 Ústav experimentálnej farmakológie a toxikológie SAV, Bratislava, Slovenska republika
|Section:||Organic, bioorganic and pharmaceutical chemistry, pharmacology|
Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase (ALR2) and its inhibitors (ARIs) have been gaining attention over the years. Although many potent ARIs have been identified, the majority of these also inhibit aldehyde reductase (ALR1), a related enzyme involved in the detoxification of reactive aldehydes. These findings are motivating for design of novel ARIs with attenuated toxicity and improved physicochemical profiles as potential therapeutic agents.
Starting from the efficient carboxymethylated tetrahydro- and hexahydropyridoindole derivatives , a series of new compounds with pyridoindole structure was synthesized and tested for the inhibition of rat lens aldose reductase. Structural modifications of the pyridoindole scaffold brought unexpected increase in efficiency. The most potent compound in this series, DPI-1, showed inhibitory activity more than 1000 times higher (IC50 = 12,6 nM), while being 780 times less active against rat ALR1 (IC50 = 9983 nM). Docking to the active site of ALR2 performed for DPI-1 revealed an interaction network responsible for the high affinity and selectivity. In ex vivo experiment, sorbitol accumulation in isolated rat eye lenses was significantly inhibited by DPI-1 in the presence of high glucose, starting at a concentration as low as 0.1 μM. This finding indicates the ready uptake of DPI-1 by the eye lens tissue followed by inhibition of the cytosolic ALR2. In streptozotocin-induced diabetic rats, DPI-1 administered intragastrically (i.g., 50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in red blood cells and the sciatic nerve. This result points to a ready uptake of DPI-1 after its i.g. administration into the central compartment, its supply to the peripheral nerves and inhibition of aldose reductase-mediated sorbitol accumulation. Molecular obesity indices, ADMET parameters predicted along with water solubility point to an excellent „lead-likeness“ of compound DPI-1.
To conclude, compound DPI-1, the lead candidate of a new series of pyridoindole derivatives was identified as a highly effective and selective aldose reductase inhibitor with a promise of targeting long-term diabetic complications.