3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel openers: effect of 6,7-disubstitution on potency and tissue selectivity.
A series of 6,7-disubstituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing a short alkylamino side chain in the 3-position were synthesized. These compounds were tested on rat pancreatic islets and on rat aorta rings. In vitro data indicated that in most cases substitution in the 6 and the 7 positions increased their activity as inhibitors of insulin secretion, while the myorelaxant potency of the drugs was maintained or enhanced according to the nature of the substituent in the 7-position. The presence of either chlorine or bromine atoms in the 6 and 7 positions did not improve the apparent selectivity of the drugs for the pancreatic tissue. By contrast, the introduction of one or two fluorine atoms, as well as the presence of a methoxy group in the 7-position, generated potent and selective inhibitors of insulin release. Radioisotopic and fluorimetric experiments performed with the most potent compound inhibiting insulin release (34, BPDZ 259, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) confirmed that the drug activated K(ATP) channels. 34 was found to be one of the most potent and selective pancreatic potassium channel openers yet described.
de Tullio
Pascal
P
Centre de Recherche en Pharmacochimie des Substances Naturelles et Synthétiques, Laboratoire de Chimie Pharmaceutique, Université de Liège, 1 Avenue de l'Hôpital, B-4000 Liège, Belgium. P.deTullio@ulg.ac.be
Boverie
Stéphane
S
Becker
Bénédicte
B
Antoine
Marie-Hélène
MH
Nguyen
Quynh-Anh
QA
Francotte
Pierre
P
Counerotte
Stéphane
S
Sebille
Sophie
S
Pirotte
Bernard
B
Lebrun
Philippe
P
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009928:Organ Specificity; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
C502993:6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D007328:Insulin; D015221:Potassium Channels; D000255:Adenosine Triphosphate