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  • 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
    Drug Metabolism and Disposition, 2010
    Co-Authors: Florian Gillotin, Bernard Pirotte, Philippe Lebrun, Pierre Francotte, Patrice Chiap, Michel Frederich, Jeanclaude Van Heugen, Pascal De Tullio
    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 phenobarbital-induced 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.

  • 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Pascal De Tullio, Bernard Pirotte, Stéphane Boverie, Marie-hélène Antoine, B. Becker, Sophie Sebille, Stéphane Counerotte, Q A Nguyen, Pierre Francotte, Philippe Lebrun
    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.

  • New insights into the development of ATP-sensitive Potassium Channel Openers
    Expert Opinion on Therapeutic Patents, 2005
    Co-Authors: Bernard Pirotte, Pascal De Tullio, Marie-hélène Antoine, Sophie Sebille, Xavier Florence, Philippe Lebrun
    Abstract:

    ATP-sensitive Potassium Channel Openers are expected to be valuable drugs for the treatment of a wide variety of pathologies. However, their clinical interest depends mainly on their tissue selectivity, which is linked to their affinity for a specific ATP-sensitive Potassium (KATP) Channel subtype. Hypertension was the first indication for KATP Channel Openers currently on the market. Recent progress in the synthesis of tissue-selective compounds led to the discovery of potential candidates for the management (prevention and/or treatment) of several pathological states such as Type 1 or Type 2 diabetes, obesity, urinary incontinence and congestive heart failure. The present report focuses on patent applications introduced between 2001 – 2004, describing original KATP Channel Openers.

  • Effect on K(ATP) Channel activation properties and tissue selectivity of the nature of the substituent in the 7- and the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides.
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Stéphane Boverie, Bernard Pirotte, Fabian Somers, Philippe Lebrun, Marie-hélène Antoine, B. Becker, Sophie Sebille, Raogo Ouedraogo, Stéphane Counerotte, Pascal De Tullio
    Abstract:

    The present work explored 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides diversely substituted in the 7-position. Those compounds, structurally related to previously described Potassium Channel Openers such as the benzothiadiazine dioxide BPDZ 73, were tested as putative K(ATP) Channel activators on the pancreatic endocrine tissue and on the vascular smooth muscle tissue. The nature of the substituent introduced in the 7-position as well as the nature of the alkylamino side chain in the 3-position strongly affected both potency and tissue selectivity of 4H-1,2,4-benzothiadiazine 1,1-dioxides. Thus, compounds bearing in the 7-position a methyl or a methoxy group or devoid of a substituent in this position, and bearing an ethyl, an isopropyl, or a cyclobutylamino group in the 3-position were found to be potent and selective inhibitors of insulin release from rat pancreatic B-cells (i.e. 10a, 10b, 12b, 12d, 22c). In contrast, 3-alkylamino-7-trifluoromethyl- (20a-c) and 3-alkylamino-7-pentyl-4H-1,2,4-benzothiadiazine 1,1-dioxides (11a,b) expressed a marked myorelaxant activity on rat aorta ring. Among the latter compounds, the 3-alkylamino-7-pentyl derivative (11a) showed a clear selectivity for the vascular smooth muscle tissue. The present work gives new insights into the role of the substituent in both the 7- and the 3-position for the design of 4H-1,2,4-benzothiadiazine 1,1-dioxide Potassium Channel Openers exhibiting different tissue selectivity profiles.

  • 3 and 4 substituted 4h pyrido 4 3 e 1 2 4 thiadiazine 1 1 dioxides as Potassium Channel Openers synthesis pharmacological evaluation and structure activity relationships
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Pascal De Tullio, Bernard Pirotte, Philippe Lebrun, Marie-hélène Antoine, Jeanine Fontaine, L Dupont, R Ouedraogo, S Khelili, Carine Maggetto, Bernard Masereel
    Abstract:

    4-N-Subsituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alkyl- and 3-(alkylamino)-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as Potassium Channel Openers on pancreatic and vascular tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure−activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic KATP Channel was proposed. According to their selectivity for the B-cell (endocrine tissue) vs the vascular (smooth muscle tissue) ionic Channel, sel...

C.j. Ohnmacht - One of the best experts on this subject based on the ideXlab platform.

C.a. Frank - One of the best experts on this subject based on the ideXlab platform.

Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.

  • 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
    Drug Metabolism and Disposition, 2010
    Co-Authors: Florian Gillotin, Bernard Pirotte, Philippe Lebrun, Pierre Francotte, Patrice Chiap, Michel Frederich, Jeanclaude Van Heugen, Pascal De Tullio
    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 phenobarbital-induced 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.

  • 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
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Pascal De Tullio, Bernard Pirotte, Stéphane Boverie, Marie-hélène Antoine, B. Becker, Sophie Sebille, Stéphane Counerotte, Q A Nguyen, Pierre Francotte, Philippe Lebrun
    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.

  • New insights into the development of ATP-sensitive Potassium Channel Openers
    Expert Opinion on Therapeutic Patents, 2005
    Co-Authors: Bernard Pirotte, Pascal De Tullio, Marie-hélène Antoine, Sophie Sebille, Xavier Florence, Philippe Lebrun
    Abstract:

    ATP-sensitive Potassium Channel Openers are expected to be valuable drugs for the treatment of a wide variety of pathologies. However, their clinical interest depends mainly on their tissue selectivity, which is linked to their affinity for a specific ATP-sensitive Potassium (KATP) Channel subtype. Hypertension was the first indication for KATP Channel Openers currently on the market. Recent progress in the synthesis of tissue-selective compounds led to the discovery of potential candidates for the management (prevention and/or treatment) of several pathological states such as Type 1 or Type 2 diabetes, obesity, urinary incontinence and congestive heart failure. The present report focuses on patent applications introduced between 2001 – 2004, describing original KATP Channel Openers.

  • Effect on K(ATP) Channel activation properties and tissue selectivity of the nature of the substituent in the 7- and the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides.
    Journal of Medicinal Chemistry, 2005
    Co-Authors: Stéphane Boverie, Bernard Pirotte, Fabian Somers, Philippe Lebrun, Marie-hélène Antoine, B. Becker, Sophie Sebille, Raogo Ouedraogo, Stéphane Counerotte, Pascal De Tullio
    Abstract:

    The present work explored 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides diversely substituted in the 7-position. Those compounds, structurally related to previously described Potassium Channel Openers such as the benzothiadiazine dioxide BPDZ 73, were tested as putative K(ATP) Channel activators on the pancreatic endocrine tissue and on the vascular smooth muscle tissue. The nature of the substituent introduced in the 7-position as well as the nature of the alkylamino side chain in the 3-position strongly affected both potency and tissue selectivity of 4H-1,2,4-benzothiadiazine 1,1-dioxides. Thus, compounds bearing in the 7-position a methyl or a methoxy group or devoid of a substituent in this position, and bearing an ethyl, an isopropyl, or a cyclobutylamino group in the 3-position were found to be potent and selective inhibitors of insulin release from rat pancreatic B-cells (i.e. 10a, 10b, 12b, 12d, 22c). In contrast, 3-alkylamino-7-trifluoromethyl- (20a-c) and 3-alkylamino-7-pentyl-4H-1,2,4-benzothiadiazine 1,1-dioxides (11a,b) expressed a marked myorelaxant activity on rat aorta ring. Among the latter compounds, the 3-alkylamino-7-pentyl derivative (11a) showed a clear selectivity for the vascular smooth muscle tissue. The present work gives new insights into the role of the substituent in both the 7- and the 3-position for the design of 4H-1,2,4-benzothiadiazine 1,1-dioxide Potassium Channel Openers exhibiting different tissue selectivity profiles.

  • 3 and 4 substituted 4h pyrido 4 3 e 1 2 4 thiadiazine 1 1 dioxides as Potassium Channel Openers synthesis pharmacological evaluation and structure activity relationships
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Pascal De Tullio, Bernard Pirotte, Philippe Lebrun, Marie-hélène Antoine, Jeanine Fontaine, L Dupont, R Ouedraogo, S Khelili, Carine Maggetto, Bernard Masereel
    Abstract:

    4-N-Subsituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alkyl- and 3-(alkylamino)-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as Potassium Channel Openers on pancreatic and vascular tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure−activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic KATP Channel was proposed. According to their selectivity for the B-cell (endocrine tissue) vs the vascular (smooth muscle tissue) ionic Channel, sel...