ATP sensitive
potassium (K(
ATP)) channels have important functions in neuroendocrine tissue, in smooth and skeletal muscle and in the heart. In pancreatic beta cells the K(
ATP) channels, which are formed by 4
ion channels (Kir6.2) and 4 regulatory
sulfonylurea receptors (SUR1), control the
glucose stimulated release of
insulin. The Kir6.2/SUR1 K(
ATP) channels are also present in the brain and in other neuroendocrine tissues. Blockers of Kir6.2/SUR1 channels, e.g.
glibenclamide and
repaglinide stimulate release of
insulin and are used for treatment of
type 2 diabetes. Openers of Kir6.2/SUR1 channels, e.g.
diazoxide, have in contrast only found limited clinical use in treatment of hypersecretion of
insulin associated with certain tumours (
insulinoma) and
genetic disorders (persistent
hyperinsulinemia and
hypoglycemia of infancy, PHHI). Recent studies have however, indicated that openers of Kir6.2/SUR1 channels could be useful in treatment of e.g. metabolic disorders and diseases of the CNS. The clinical use of
diazoxide has been hampered by its lack of potency and selectivity giving rise to side effects, such as oedema and
hirsutism and new selective openers of Kir6.2/SUR1 channels have been pursued. This has provided several structurally diverse series, which include 1,2,4-thiadiazine 1,1-dioxide derivatives, like
BPDZ 62,
BPDZ 73, NNC 55-0462,
NNC 55-0118 and NN414, cyanoguanidines, nitropyrazoles and 4-sulfamoylphenylbenzamides. NN414 has been shown to be a potent and Kir6.2/SUR1 selective K(
ATP) channels opener, which inhibits
glucose stimulated
insulin release in vitro and in vivo and which has beneficial effects on
glucose homeostasis in preclinical and clinical studies.