Heterocyclic scaffolds of natural as well as synthetic origin provide almost all categories of drugs exhibiting a wide range of pharmacological activities, such as antibiotics, antidiabetic and anticancer agents, and so on. Under normal homeostasis, aldose reductase 2 (ALR2) regulates vital metabolic functions; however, in pathological conditions like diabetes, ALR2 is unable to function and leads to secondary diabetic complications. ALR2 inhibitors are a novel target for the treatment of retinopathy (cataract) influenced by diabetes. Epalrestat (stat), an ALR2 inhibitor, is the only drug candidate that was approved in the last four decades; the other drugs from the stat class were retracted after clinical trial studies due to untoward iatrogenic effects. The present study summarizes the recent development (2014 and onwards) of this pharmacologically active ALR2 heterocyclic scaffold and illustrates the rationale behind the design, structure-activity relationships, and biological studies performed on these molecules. The aim of the current review is to pave a straight path for medicinal chemists and chemical biologists, and, in general, to the drug discovery scientists to facilitate the synthesis and development of novel ALR2 inhibitors that may serve as lead molecules for the treatment of diseases related to the ALR2 enzyme.diabetic-related complications (cataract), novel heterocyclic scaffolds, structure-activity relationship studies, synthetic aldose reductase 2 inhibitors
| INTRODUCTIONDiabetes mellitus (DM) is an autoimmune metabolic disorder mainly characterized by hyperglycemia which occurs due to impairment in normal blood glucose homeostasis. In DM, there is either no secretion of insulin by the islet of pancreatic β cells or diminished response to glucose by secreted insulin in the body. [1] Diabetes is of two types that is, insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus also termed type 1 and type 2 DM, respectively. Pathophysiological conditions that induce DM include autoimmune imbalance, hormonal as well as the sedentary lifestyle of an individual, additionally urbanization, and exposure to harmful chemicals are other causes of disease. [2] Blood glucose homeostasis is regulated by several hormones. However, insulin and glucagon predominantly performed aforesaid functions. [3] Insulin reduces excess blood sugar levels either by inhibiting glucose synthesis by the liver or by increasing peripheral glucose utilization through the liver, skeletal muscles, and adipose tissues.
