Towards selective Kir6.2/SUR1 potassium channel openers, medicinal chemistry and therapeutic perspectives.
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.
Medicinal Chemistry, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malov, Denmark. jbha@novonordisk.com
John Bondo
JB
Hansen
D018528:ATP-Binding Cassette Transporters / Q000819:agonists* / Q000187:drug effects*; D000577:Amides / Q000627:therapeutic use; D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use; D001581:Benzothiadiazines / Q000627:therapeutic use; D044903:Congenital Hyperinsulinism / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D003981:Diazoxide / Q000627:therapeutic use*; D005260:Female; D006146:Guanidines; D006801:Humans; D009570:Nitriles / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy; D015221:Potassium Channels / Q000819:agonists* / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists* / Q000187:drug effects*; D011955:Receptors, Drug / Q000819:agonists* / Q000187:drug effects*; D064233:Sulfonylurea Receptors; D013829:Thiadiazines / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use*; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001578:Benzopyrans; D001581:Benzothiadiazines; D003981:Diazoxide; D006146:Guanidines; D009570:Nitriles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013829:Thiadiazines; D014665:Vasodilator Agents; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human