title: New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells.
abstract: Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K(ATP) channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues of 1a. Several compounds, e.g., 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1h), were found to be potent openers of Kir6.2/SUR1 K(ATP) channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC(50) = 0.04 +/- 0.01 muM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED(50) = 4.0 mg/kg). Structural modifications of this series of K(ATP) channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.
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: Søren
authors.initials: S
authors.lastname: Ebdrup
authors.forename: Anette Frost
authors.initials: AF
authors.lastname: Jensen
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Thora B
authors.initials: TB
authors.lastname: Bodvarsdottir
authors.forename: Carsten
authors.initials: C
authors.lastname: Stidsen
authors.forename: Anne
authors.initials: A
authors.lastname: Worsaae
authors.forename: Harrie C M
authors.initials: HC
authors.lastname: Boonen
authors.forename: Per O G
authors.initials: PO
authors.lastname: Arkhammar
authors.forename: Tinna
authors.initials: T
authors.lastname: Fremming
authors.forename: Philip
authors.initials: P
authors.lastname: Wahl
authors.forename: Hanne T
authors.initials: HT
authors.lastname: Kornø
authors.forename: J Bondo
authors.initials: JB
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011924:Rats, Zucker; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D013829:Thiadiazines; D000099161:Kcnj11 Channel; C513154:6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno(3,2-e)-1,2,4-thiadiazine; C475618:NN 414