title: Synthesis and evaluation of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives as K(ATP) channel agonists.
abstract: A series of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives has been synthesized and evaluated as K(ATP) channel agonists using the inside-out excised patch clamp technique. The most active compounds were approximately 20-fold more potent than diazoxide in opening K(ATP) channels. A linear relationship exists between the potency of the compound and the sigma value of the 7-substituent with electron-withdrawing groups exhibiting higher activity. These compounds may be useful in modulating insulin release from pancreatic beta-cells and in diseases associated with hyperinsulinemia.
authors.affiliation: GlaxoSmithKline Research and Development, 5Moore Drive, Research Triangle Park, NC 27709, USA. ajp25551@gsk.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Claire
authors.initials: C
authors.lastname: Townsend
authors.forename: Jennings F
authors.initials: JF
authors.lastname: Worley
authors.forename: Scott H
authors.initials: SH
authors.lastname: Allen
authors.forename: Dulce
authors.initials: D
authors.lastname: Garrido
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mertz
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Pfohl
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Terry
authors.forename: Jim F
authors.initials: JF
authors.lastname: Truax
authors.forename: Robert L
authors.initials: RL
authors.lastname: Veasey
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Thomson
mesh_terms: D018528:ATP-Binding Cassette Transporters; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004583:Electrons; D004594:Electrophysiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D054086:KATP Channels; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D011522:Protons; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D018528:ATP-Binding Cassette Transporters; D001581:Benzothiadiazines; D007328:Insulin; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011522:Protons; C092520:uK-ATP-1 potassium channel