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Pierre Lestage - One of the best experts on this subject based on the ideXlab platform.
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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
ACS Chemical Neuroscience, 2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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 G...
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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
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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
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synthesis pharmacological and structural characterization and thermodynamic aspects of glua2 positive allosteric modulators with a 3 4 dihydro 2h 1 2 4 benzothiadiazine 1 1 dioxide scaffold
Journal of Medicinal Chemistry, 2013Co-Authors: Annbeth Norholm, Eric Goffin, L. Danober, Pierre Francotte, Karla Frydenvang, Lars Olsen, Christian Krintel, Sylvie Challal, Iuliana Botezpop, Pierre LestageAbstract:Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the Cyclopropyl Group of 3 and the backbone of Phe495 and Met496.
B E Abboaoffei - One of the best experts on this subject based on the ideXlab platform.
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synthesis of novel potent dipeptidyl peptidase iv inhibitors with enhanced chemical stability interplay between the n terminal amino acid alkyl side chain and the Cyclopropyl Group of α aminoacyl l cis 4 5 methanoprolinenitrile based inhibitors
Journal of Medicinal Chemistry, 2004Co-Authors: David R Magnin, Jeffrey A Robl, Richard B Sulsky, David J Augeri, Yanting Huang, Ligaya M Simpkins, Prakash Taunk, David A Betebenner, James G Robertson, B E AbboaoffeiAbstract:A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a Cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
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synthesis of novel potent dipeptidyl peptidase iv inhibitors with enhanced chemical stability interplay between the n terminal amino acid alkyl side chain and the Cyclopropyl Group of α aminoacyl l cis 4 5 methanoprolinenitrile based inhibitors
Journal of Medicinal Chemistry, 2004Co-Authors: David R Magnin, Jeffrey A Robl, Richard B Sulsky, David J Augeri, Yanting Huang, Ligaya M Simpkins, Prakash Taunk, David A Betebenner, James G Robertson, B E AbboaoffeiAbstract:A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a Cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with β-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucos...
Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.
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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
ACS Chemical Neuroscience, 2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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 G...
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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
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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
L. Danober - One of the best experts on this subject based on the ideXlab platform.
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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
ACS Chemical Neuroscience, 2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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 G...
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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
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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
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synthesis pharmacological and structural characterization and thermodynamic aspects of glua2 positive allosteric modulators with a 3 4 dihydro 2h 1 2 4 benzothiadiazine 1 1 dioxide scaffold
Journal of Medicinal Chemistry, 2013Co-Authors: Annbeth Norholm, Eric Goffin, L. Danober, Pierre Francotte, Karla Frydenvang, Lars Olsen, Christian Krintel, Sylvie Challal, Iuliana Botezpop, Pierre LestageAbstract:Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the Cyclopropyl Group of 3 and the backbone of Phe495 and Met496.
Pierre Francotte - One of the best experts on this subject based on the ideXlab platform.
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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
ACS Chemical Neuroscience, 2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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 G...
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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
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract: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
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synthesis pharmacological and structural characterization and thermodynamic aspects of glua2 positive allosteric modulators with a 3 4 dihydro 2h 1 2 4 benzothiadiazine 1 1 dioxide scaffold
Journal of Medicinal Chemistry, 2013Co-Authors: Annbeth Norholm, Eric Goffin, L. Danober, Pierre Francotte, Karla Frydenvang, Lars Olsen, Christian Krintel, Sylvie Challal, Iuliana Botezpop, Pierre LestageAbstract:Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the Cyclopropyl Group of 3 and the backbone of Phe495 and Met496.
