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Pascal De Tullio - One of the best experts on this subject based on the ideXlab platform.

  • 7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-Benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars Olsen
    Abstract:

    We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most Benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first Benzothiadiazine dioxide AMPApam to reach the nanomolar range.

  • 7‑Phenoxy-Substituted 3,4-Dihydro‑2H‑1,2,4-Benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
    2017
    Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars Olsen
    Abstract:

    We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2­(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most Benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first Benzothiadiazine dioxide AMPApam to reach the nanomolar range

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Fabian Somers, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminoBenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-Benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves Thomas
    Abstract:

    Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described Benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-Benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising Benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.

  • Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
    2014
    Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves Thomas
    Abstract:

    Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described Benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-Benzothiadiazine 1,1-dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising Benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg

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

  • Synthesis, characterization, and investigation of the antioxidant activity of some 1,2,4-Benzothiadiazine-1,1-dioxides bearing sulfonylthioureas moieties
    Canadian Journal of Chemistry, 2019
    Co-Authors: Kamel Harrouche, Bernard Pirotte, Asma Lahouel, Mebrouk Belghobsi, S. Khelili
    Abstract:

    A series of 1,2,4-Benzothiadiazine-1,1-dioxides bearing a sulfonylthiourea moiety were synthesized, characterized, and screened for their antioxidant activity, using six antioxidant analytical assa...

  • Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-Benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
    2016
    Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard Pirotte
    Abstract:

    Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)­propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted Benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-Benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-Benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Fabian Somers, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminoBenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-Benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 Benzothiadiazine 1 1 dioxides toward an improvement in sulfonylurea receptor 1 selectivity and metabolism sta
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminoBenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-Benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

  • Impact of the nature of the substituent at the 3-position of 4H-1,2,4-Benzothiadiazine 1,1-dioxides on their opening activity toward ATP-sensitive potassium channels.
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Bernard Pirotte, Pascal De Tullio, Stéphane Boverie, Catherine Michaux, Philippe Lebrun
    Abstract:

    The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-Benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-Benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of Benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-Benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-Benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.

Philippe Lebrun - One of the best experts on this subject based on the ideXlab platform.

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Fabian Somers, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminoBenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-Benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 Benzothiadiazine 1 1 dioxides toward an improvement in sulfonylurea receptor 1 selectivity and metabolism sta
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminoBenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-Benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

  • Impact of the nature of the substituent at the 3-position of 4H-1,2,4-Benzothiadiazine 1,1-dioxides on their opening activity toward ATP-sensitive potassium channels.
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Bernard Pirotte, Pascal De Tullio, Stéphane Boverie, Catherine Michaux, Philippe Lebrun
    Abstract:

    The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-Benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-Benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of Benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-Benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-Benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.

  • 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.

  • Effect on insulin release of compounds structurally related to the potassium-channel opener 7-chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (BPDZ 73): introduction of heteroatoms on the 3-alkylamino side chain of the Benzothiadiazine
    Journal of Pharmacy and Pharmacology, 2001
    Co-Authors: Stéphane Boverie, Pascal De Tullio, Fabian Somers, Philippe Lebrun, Marie-hélène Antoine, B. Becker, Sophie Sebille, Bernard Pirotte
    Abstract:

    7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-Benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-Benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.

Pierre Fraikin - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-Benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
    2016
    Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard Pirotte
    Abstract:

    Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)­propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted Benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-Benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-Benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency

  • positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves Thomas
    Abstract:

    Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described Benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-Benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising Benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.

  • Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
    2014
    Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves Thomas
    Abstract:

    Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described Benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-Benzothiadiazine 1,1-dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising Benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg

  • new fluorinated 1 2 4 Benzothiadiazine 1 1 dioxides discovery of an orally active cognitive enhancer acting through potentiation of the 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors
    Journal of Medicinal Chemistry, 2010
    Co-Authors: Pierre Francotte, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Jeanyves Thomas, Florian Gillotin, Patrice Chiap, Jeanclaude Van Heugen, Danielhenri Caignard
    Abstract:

    In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA recept...

  • Chloro-substituted 3-alkylamino-4h-1,2,4-Benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel activators: Impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity
    Journal of Medicinal Chemistry, 2010
    Co-Authors: Bernard Pirotte, Pierre Fraikin, Xavier Florence, Philip Wahl, Quynh Anh Nguyen, John Bondo Hansen, Pascal De Tullio, Fabian Somers, Pierre Lebrun
    Abstract:

    The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-Benzothiadiazine 1,1-dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.

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