Chloro-substituted 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel activators: impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity.
The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.
Pirotte
Bernard
B
Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Medicament (Drug Research Center), Universite de Liege, 1 Avenue de l'Hopital, B-4000 Liege, Belgium. B.Pirotte@ulg.ac.be
de Tullio
Pascal
P
Nguyen
Quynh-Anh
QA
Somers
Fabian
F
Fraikin
Pierre
P
Florence
Xavier
X
Wahl
Philip
P
Hansen
John Bondo
JB
Lebrun
Philippe
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002713:Chlorine / Q000737:chemistry*; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003981:Diazoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism
C546797:6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide; C546796:8-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D007328:Insulin; D015221:Potassium Channels; D002713:Chlorine; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide