Aldose reductase (AKR1B1) is an important enzyme in the polyol pathway that has been associated with diabetic complications. Inhibition of AKR1B1 is complicated by side effects that arise from secondary action of AKR1B1 inhibition on antioxidant defense in the body, such as reduction of the toxic aldehyde 4-hydroxy-2,3-nonenal (HNE).
This study investigated Pyrazolo[1,5-a]pyrimidine derivatives to identify inhibitors that specifically target the polyol pathway (aldose reductase differential inhibitors – ARDIs). This was identified by preferential reduction in L-idose (from Carbosynth - MI04205) or GS-HNE, rather than HNE. L-idose was chosen as an alternative to D-glucose and substrate for AKR1B1 to indicate alteration in the polyol pathway, as opposed to the antioxidant defense pathway. The derivative 4-(4-chlorobenzyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid was considered to have the most differential inhibitor activity, with preferential reduction of L-idose, compared to HNE. The therapeutic potential of this lead compound, for treating diabetic complications, requires further investigation.
For further information, please refer to the paper: Balestri et al, 2018.