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 oil 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 oil both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active oil 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-ispropylamino-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 oil HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC50 = 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/Kir-6.2 K-ATP channels.