Selectivity Challenges for Aldose Reductase Inhibitors: A Review on Comparative SAR and Interaction Studies

Chronic hyperglycemia initiates multiple pathways that contribute to developing complications in individuals with diabetes, ultimately leading to significant health problems and mortality. The extensive research elucidated the pathophysiological role of aldose reductase (ALR2) in the polyol pathway, which significantly contributes to these diabetic complications. ALR2, a rate-limiting enzyme in this pathway, becomes overactive in hyperglycemic conditions and plays a central role in developing diabetic complications. As a result, inhibiting ALR2 has emerged as a promising approach for managing these complications. Despite numerous ALR2 inhibitors, only epalrestat is currently marketed, mainly due to challenges related to their limited selectivity for ALR2 over aldehyde reductase (ALR1). This selectivity issue arises because ALR2 shares 65% structural similarity with ALR1, leading to concerns about potential toxicity. This article provides a detailed overview of the advancements made in the last decade (2012-2023) in developing ALR2 and ALR1 inhibitors, addressing the selectivity challenges between ALR2 and ALR1 through comparative structure-activity relationship (SAR) analyses. It also explores the intricate interactions of potent ligands within the catalytic sites of both ALR2 and ALR1, offering innovative strategies for designing target-specific ALR2 inhibitors to minimize off-target toxicity.