Pterin-7-carboxamides as a new class of aldose reductase inhibitors.

Aldose reductase is related to the onset and progression of diabetic complications, such as neuropathy, retinopathy, angiopathy, and so on: therefore molecules that are capable of inhibiting the enzyme are potential drugs for treatment of diabetic complications. Epalrestat is the sole aldose reductase inhibitor that is clinically used, but still has some drawbacks. Thus, the development of new aldose reductase inhibitors is still desired. We have synthesized a series of new pterin-7-carboxamides, and evaluated their in vitro inhibitory activities against human aldose reductase. All newly synthesized compounds exhibited the inhibitory activity. Among them, 1a having a glycine side chain exhibits the highest activity comparable to that of sorbinil, a highly active aldose reductase inhibitor. Molecular docking of 1a on the active site of the enzyme indicated this compound interacts with amino acid residues that are specific to the enzyme and related to suppressing side effects. Based on these results, we proved perin-7-carboxamides to be a new class of aldose reductase inhibitors, and particularly compound 1a was found to be a good candidate for further biological investigations as a drug for treatment of diabetic complications with fewer side effects.