3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides as ATP-Sensitive Potassium Channel Openers:  Effect of 6,7-Disubstitution on Potency and Tissue Selectivity

Abstract

A series of 6,7-disubstituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing a short alkylamino side chain in the 3-position were synthesized. These compounds were tested on rat pancreatic islets and on rat aorta rings. In vitro data indicated that in most cases substitution in the 6 and the 7 positions increased their activity as inhibitors of insulin secretion, while the myorelaxant potency of the drugs was maintained or enhanced according to the nature of the substituent in the 7-position. The presence of either chlorine or bromine atoms in the 6 and 7 positions did not improve the apparent selectivity of the drugs for the pancreatic tissue. By contrast, the introduction of one or two fluorine atoms, as well as the presence of a methoxy group in the 7-position, generated potent and selective inhibitors of insulin release. Radioisotopic and fluorimetric experiments performed with the most potent compound inhibiting insulin release (34, BPDZ 259, 6-chloro-7-fluoro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide) confirmed that the drug activated K(ATP) channels. 34 was found to be one of the most potent and selective pancreatic potassium channel openers yet described.

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.…”

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

“…The reported series [38] consists of substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides bearing in most cases, a short alkylamino side chain in the 3-position ( Figure 1). These compounds along with their activity values for rat pancreatic islets and rat aorta rings are compiled in Table I.…”

“…Recently, a series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides was reported [38] and were tested as putative K ATP channel openers on a vascular and a pancreatic pharmacological model in order to evaluate their potency and tissue selectivity. The initial structure-activity relationship (SAR) study on these compounds was, however, directed only to alteration of the substituents at different positions of the structure but no rationale was provided to reduce the trial-and-error factors.…”

Synthesis of Modified 4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides and Determination of their Affinity and Selectivity for Different Types of KATP Channels

“…In contrast to our results, where we observed similar potencies with compounds 1 a and 7, de Tullio and co-workers reported a fivefold increase in potency (measured in a SUR2B test system) for diazoxide analogues 2 substituted with an isopropyl-amino side chain in position 3 when the 7-chloro was replaced by a 7-bromo substituent. [23] As indicated by the data given in Table 1 (entry 5), the 7-phenyl-substituted analogue 8 loses activity by one order of magnitude compared with diazoxide (1 a). Obviously, the phenyl substituent in C-7 position appears to substantially hinder receptor binding and activation due to steric demand or electronic properties.…”