[1,2,4]triazino[4,3-a]benzimidazole acetic acid derivatives: A new class of selective aldose reductase inhibitors

Acetic acid derivatives of [1,2,4]triazino[4,3-alpha ]benzimidazole (TBI) w ere synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-alph a ]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhib itory activity (IC50 = 0.36 muM) and was found to be effective in preventin g cataract development in severely galactosemic rats when administered as a n eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehy drogenase, or glutathione reductase. The activity of 3 was lowered by inser ting various substituents on the pendant phenyl ring, by shifting the aceti c acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleavi ng the TBI system to yield benzimidazolylidenehydrazines as open-chain anal ogues. A three-dimensional model of human ALR2 was built, taking into accou nt the conformational. changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-acti vity relationships in the TBI series and will guide the design of novel ALR 2 inhibitors.