Characterization and functional effects of cemtirestat a potent aldo keto reductase inhibitor in diabetes and inflammation

Aldo-keto reductases (AKR) are NAD(P)H dependent oxidoreductases that have been best characterized as glucose reducing agents, and have been implicated in diabetic pathophysiology. The first enzyme of the polyol pathway, aldose reductase (AKR1B1) is involved in the molecular mechanisms of glucose toxicity leading to diabetic complications, including microvascular, neurological, and macrovascular disorders, which are responsible for significant increase in morbidity and mortality of diabetic patients. These enzymes are also known to mediate an inflammatory response to lipid peroxidation metabolic products. Since chronic inflammation is associated with a number of pathological states, AKR1B1 has been implicated in various inflammatory diseases such as atherosclerosis, asthma, uveitis, sepsis, arthritis, periodontitis and several types of cancer related to chronic inflammation. Recently novel aldose reductase inhibitors based on carboxymethylated mercapto-triazino-indole scaffold have been designed [1]. Among the novel compounds, cemtirestat (Fig. 1) was the most promising inhibitor, with an IC50 in submicromolar range and high selectivity