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

Abstract

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 microM) associated with a weak vasorelaxant effect (ED(50) > 300 microM), 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 microM), was found to be very potent on vascular smooth muscle cells (ED(50) = 0.29 microM). 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.

N-Aryl-N′-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis

“…To confirm or refute the possible link between the K ATP -channelopening potency of drugs and their growth inhibitory activity, we tested several reference compounds known to be K ATP -channel openers or blockers. Thus, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (a strong SUR1-type K ATPchannel opener [19]), 7-chloro-3-(1,1-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide (expected to be a SUR2B-type K ATP -channel opener [20]), R/S-pinacidil (a SUR2B-type K ATPchannel opener), and glibenclamide (a K ATP -channel blocker) were assayed in terms of glioma growth inhibitory activity by means of the MTT colorimetric assay in human U373 glioblastoma cells. None of these reference compounds (three openers and one blocker) expressed a marked growth inhibitory activity (IC 50 > 100 mM) (data not shown), supporting the view that K ATP channels were probably not involved in the in vitro anti-glioma growth inhibitory activity of arylurea-and arylthiourea-type chromans.…”

Crystal structure of 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide, C10H12ClN3O2S

“…Discussion 7-Chloro-3-isopropylamino-4f/-1,2,4-benzothiadiazine 1,1 -dioxide, namely BPDZ73, was revealed to be one of the most potent and tissue-selective pancreatic B-cells ATP sensitive potassium channel opener [1,2]. Some crystallographic structures of related compounds have been determined such as 7-iodo-3-isopropylamino-4/M ,2,4-benzothiadiazine 1,1-dioxide (BPDZ69) [3] which is less powerful and less sensitive at the level of the pancreatic tissue.…”

“…The compound was synthesized by a well described four steps chemical pathway starting from 4-chloroaniline [1]. Crystals were obtained by slow evaporation of a methanol solution.…”

Quantitative structure-activity relationship study of ATP-sensitive potassium channel openers: Derivatives of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide

“…In the search for new pancreatic-selective PCOs, a series comprising of 3-alkylamino-4H-pyridoand 2 1,2,4-benzothiadiazine 1,1-dioxides has been developed; among them BPDZ 44 [34], BPDZ 73 [35], BPDZ 138 [36] and BPDZ 216 [37] were identified as the first potent and selective pancreatic K ATP channel openers.…”