Toward Tissue-Selective Pancreatic B-Cells K_(ATP) Channel Openers Belonging to 3-Alkylamino-7-halo-4H-1,2,4-benzothiadiazine 1,1-Dioxides

3-(Alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides were synthesized, and their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K_(ATP) channel activators diazoxide and pinacidil. Structure-activity relationships indicated that an improved potency and selectivity for the pancreatic tissue was obtained by introducing a fluorine atom in the 7-position and a short linear (preferably ethyl) or cyclic (preferably cyclobutyl) hydrocarbon chain on the nitrogen atom in the 3-position. By contrast, strong myorelaxant activity was gained by the introduction of a halogen atom different from the fluorine atom in the 7-position and a bulky branched alkylamino chain in the 3-position. Thus, 3-(ethylamino)-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide (11) expressed a marked inhibitory activity on pancreatic B-cells (IC_(50) = 1 μM) associated with a weak vasorelaxant effect (ED_(50) > 300 μM), whereas 7-chloro-3-(1,1-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide (27), which was only slightly active on insulin-secreting cells (IC_(50) > 10 μM), was found to be very potent on vascular smooth muscle cells (ED_(50) = 0.29 μM). Radioisotopic and electrophysiological investigations performed with 7-chlorinated, 7-iodinated, and 7-fluorinated 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides confirmed that the drugs activated K_(ATP) channels. The present data revealed that subtle structural modifications of 3-(alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides can generate original compounds activating K_(ATP) channels and exhibiting different in vitro tissue selectivity profiles.

作 者：

Pascal de Tullio；Benedicte Becker；Stephane Boverie；Michael Dabrowski；Philip Wahl；Marie-Helene Antoine；Fabian Somers；Sophie Sebille；Raogo Ouedraogo；John Bondo Hansen

刊 名：

Journal of Medicinal Chemistry 

年，卷(期)：

2003vol.46(no.15) 

分类号：

 

关键词：

正文语种：

eng 

基金项目：