Selective pancreatic ATP-sensitive-potassium channel openers for the treatment of glucose homeostasis disorder

Abstract

Disorders of glucose homeostasis may be associated with severe pathologies such as type 1 and type 2 diabetes, insulinoma, persistent hyperinsulinemic hypoglycemia of infancy (PHHI), polycystic ovary syndrome (PCOS) and/or obesity. Specific activation of the Kir6.2/SUR1 K ATP channel subtype has been shown to be beneficial for the treatment of these pathologies. Starting from diazoxide, a nonselective Kir6.2/SUR1 K ATP channel activator, many research groups have conducted searches in an attempt to discover more potent and selective drugs. Several 3-alkylaminoarylthiadiazine 1,1-dioxides (BPDZ-44, BPDZ-73, BPDZ-415, NNC-55-0118, NN-414) have been described as potent Kir6.2/SUR1 K ATP channel openers and are reported to inhibit insulin release without a pronounced effect on smooth muscle mechanical activity NN-414 was the most extensively studied drug and had entered clinical trials, although its development was discontinued due to liver toxicity. Other chemical series have also been developed, but none has led to compounds as potent and/or as selective as the lead arylthiadiazine drugs. Based on the therapeutic interest of Kir6.2/SUR1 K ATP channel activators, the discovery of new series with improved pharmacodynamic and/or pharmacokinetic properties remains a priority.