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

J Med Chem. 2010 Jan 14;53(1):147-54. doi: 10.1021/jm9010093.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Benzothiadiazines / chemical synthesis
  • Benzothiadiazines / chemistry
  • Benzothiadiazines / pharmacology*
  • Cell Line
  • Chlorine / chemistry*
  • Cyclic S-Oxides / chemical synthesis
  • Cyclic S-Oxides / chemistry
  • Cyclic S-Oxides / pharmacology*
  • Diazoxide / analogs & derivatives*
  • Diazoxide / chemistry
  • Diazoxide / pharmacology*
  • Drug Evaluation, Preclinical
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Molecular Structure
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Potassium Channels / drug effects*
  • Potassium Channels / metabolism
  • Rats
  • Stereoisomerism


  • 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
  • 8-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide
  • Benzothiadiazines
  • Cyclic S-Oxides
  • Insulin
  • Potassium Channels
  • Chlorine
  • Adenosine Triphosphate
  • Glucose
  • Diazoxide