A pyridothiadiazine (BPDZ 44) as a new and potent activator of ATP-sensitive K+ channels

Pirotte, Bernard; Antoine, Marie-Hélène; Tullio, Pascal De; Hermann, Marcel; Herchuelz, André; Delarge, J.; Lebrun, Philippe

doi:10.1016/0006-2952(94)90337-9

Cited by 33 publications

(43 citation statements)

References 9 publications

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“…Among these drugs, BPDZ 44 (1), BPDZ 73 (2), BPDZ 154 (3), BPDZ 157 (4), BPDZ 415 (5), and BPDZ 256 (6) ( Fig. 1) were identified as potent and selective pancreatic PCOs (Pirotte et al, 1994;de Tullio et al, 2003de Tullio et al, , 2005. However, despite their excellent in vitro profiles, many of these compounds exhibited unexpected in vivo results in terms of potency and/or side effects.…”

supporting

confidence: 76%

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Gillotin

Chiap

Frédérich

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity, and hyperinsulinemia. Taking into account these promising therapeutic benefits, different series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide were developed. In view of the lead optimization process of the series, knowledge of absorption, distribution, metabolism, excretion, and toxicity parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds [7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 73) and 7-chloro-3-(3-pentylamino)-4H-1,2,4-benzothiadiazine 1,1-dioxide (BPDZ 157)] were incubated in the presence of phenobarbitalinduced rat liver microsomes to produce expected mammal in vivo phase I metabolites. The resulting major metabolites were then analyzed by both mass spectrometry (MS) and NMR to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of nontreated rats and human microsomes to compare the metabolic profiles. In the present study, the combined use of an exact mass liquid chromatography (LC)/tandem MS platform and an LC/solid-phase extraction/NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCO drugs. These results greatly help the optimization of the lead compounds.

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supporting

confidence: 76%

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Gillotin

Chiap

Frédérich

et al. 2010

Drug Metabolism and Disposition

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“…BPDZ 44 (Fig. 1) is a compound structurally related to both diazoxide and pinacidil and which has previously been shown to be a potent and specific activator of the beta-cell K + ATP channel [18]. Direct confirmation that verapamil modulates K + ATP channels was obtained by single-channel patch-clamp recordings, which revealed that verapamil elicited a dose-dependent inhibition of the K + ATP currents.…”

Section: Discussionmentioning

confidence: 92%

“…Effects of verapamil on BPDZ 44-induced changes in 86 Rb outflow. As previously described [18], the K + ATP channel opener BPDZ 44 (50 mmol/l) increased 86 Rb FOR from islets perifused in the presence of 5.6 mmol/l glucose and extracellular Ca 2 + (Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

Verapamil, a phenylalkylamine Ca 2 + channel blocker, inhibits ATP-sensitive K + channels in insulin-secreting cells from rats

et al. 1997

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Sharma¹,

Singh²,

Sharma³

2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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A pyridothiadiazine (BPDZ 44) as a new and potent activator of ATP-sensitive K+ channels

Cited by 33 publications

References 9 publications

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

Verapamil, a phenylalkylamine Ca 2 + channel blocker, inhibits ATP-sensitive K + channels in insulin-secreting cells from rats

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

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