title: 6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells.
abstract: 6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.
authors.affiliation: Novo Nordisk Research and Development, Novo Nordisk Park, DK 2760 Måløv, Denmark.
authors.forename: Flemming E
authors.initials: FE
authors.lastname: Nielsen
authors.forename: Thora B
authors.initials: TB
authors.lastname: Bodvarsdottir
authors.forename: Anne
authors.initials: A
authors.lastname: Worsaae
authors.forename: Peter
authors.initials: P
authors.lastname: MacKay
authors.forename: Carsten E
authors.initials: CE
authors.lastname: Stidsen
authors.forename: Harrie C M
authors.initials: HC
authors.lastname: Boonen
authors.forename: Lone
authors.initials: L
authors.lastname: Pridal
authors.forename: Per O G
authors.initials: PO
authors.lastname: Arkhammar
authors.forename: Philip
authors.initials: P
authors.lastname: Wahl
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Finn
authors.initials: F
authors.lastname: Junager
authors.forename: Nils
authors.initials: N
authors.lastname: Dragsted
authors.forename: Tina M
authors.initials: TM
authors.lastname: Tagmose
authors.forename: John P
authors.initials: JP
authors.lastname: Mogensen
authors.forename: Anette
authors.initials: A
authors.lastname: Koch
authors.forename: Svend P
authors.initials: SP
authors.lastname: Treppendahl
authors.forename: J Bondo
authors.initials: JB
authors.lastname: Hansen
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002460:Cell Line; D005260:Female; D005947:Glucose; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000819:agonists* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011955:Receptors, Drug; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013829:Thiadiazines; D000255:Adenosine Triphosphate; D005947:Glucose