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-benzothiadiazine 1,1-Dioxides

Pierre Francotte; Ann-Beth Nørholm; Taru Deva; Lars Olsen; Karla Frydenvang; Eric Goffin; Pierre Fraikin; Pascal de Tullio; Sylvie Challal; Jean-Yves Thomas; Fabrice Iop; Caroline Louis; Iuliana Botez-Pop; Pierre Lestage; Laurence Danober; Jette Sandholm Jensen Kastrup; Bernard Pirotte

doi:10.1021/jm501268r

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-benzothiadiazine 1,1-Dioxides

Pierre Francotte, Ann-Beth Nørholm, Taru Deva, Lars Olsen, Karla Frydenvang, Eric Goffin, Pierre Fraikin, Pascal de Tullio, Sylvie Challal, Jean-Yves Thomas, Fabrice Iop, Caroline Louis, Iuliana Botez-Pop, Pierre Lestage, Laurence Danober, Jette Sandholm Jensen Kastrup, Bernard Pirotte

17 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	22
Pages (from-to)	9539-53
Number of pages	15
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm501268r
Publication status	Published - 26 Nov 2014

Keywords

Allosteric Site
Animals
Benzothiadiazines
Calorimetry
Chemistry, Pharmaceutical
Crystallography, X-Ray
Cyclic S-Oxides
Dimerization
Drug Design
Electrophysiology
Hippocampus
Humans
Hydrogen
Kinetics
Mice
Oxides
Propionates
Protein Binding
Rats
Rats, Wistar
Receptors, AMPA
Temperature
Thermodynamics
Thiadiazines

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Francotte, P., Nørholm, A.-B., Deva, T., Olsen, L., Frydenvang, K., Goffin, E., Fraikin, P., de Tullio, P., Challal, S., Thomas, J.-Y., Iop, F., Louis, C., Botez-Pop, I., Lestage, P., Danober, L., Kastrup, J. S. J., & Pirotte, B. (2014). 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-benzothiadiazine 1,1-Dioxides. Journal of Medicinal Chemistry, 57(22), 9539-53. https://doi.org/10.1021/jm501268r

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-benzothiadiazine 1,1-Dioxides. / Francotte, Pierre; Nørholm, Ann-Beth; Deva, Taru et al.
In: Journal of Medicinal Chemistry, Vol. 57, No. 22, 26.11.2014, p. 9539-53.

Research output: Contribution to journal › Journal article › Research › peer-review

Francotte, P, Nørholm, A-B, Deva, T, Olsen, L, Frydenvang, K, Goffin, E, Fraikin, P, de Tullio, P, Challal, S, Thomas, J-Y, Iop, F, Louis, C, Botez-Pop, I, Lestage, P, Danober, L, Kastrup, JSJ & Pirotte, B 2014, '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-benzothiadiazine 1,1-Dioxides', Journal of Medicinal Chemistry, vol. 57, no. 22, pp. 9539-53. https://doi.org/10.1021/jm501268r

Francotte P, Nørholm AB, Deva T, Olsen L, Frydenvang K, Goffin E et al. 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-benzothiadiazine 1,1-Dioxides. Journal of Medicinal Chemistry. 2014 Nov 26;57(22):9539-53. doi: 10.1021/jm501268r

Francotte, Pierre ; Nørholm, Ann-Beth ; Deva, Taru et al. / 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-benzothiadiazine 1,1-Dioxides. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 22. pp. 9539-53.

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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.",

keywords = "Allosteric Site, Animals, Benzothiadiazines, Calorimetry, Chemistry, Pharmaceutical, Crystallography, X-Ray, Cyclic S-Oxides, Dimerization, Drug Design, Electrophysiology, Hippocampus, Humans, Hydrogen, Kinetics, Mice, Oxides, Propionates, Protein Binding, Rats, Rats, Wistar, Receptors, AMPA, Temperature, Thermodynamics, Thiadiazines",

author = "Pierre Francotte and Ann-Beth N{\o}rholm and Taru Deva and Lars Olsen and Karla Frydenvang and Eric Goffin and Pierre Fraikin and {de Tullio}, Pascal and Sylvie Challal and Jean-Yves Thomas and Fabrice Iop and Caroline Louis and Iuliana Botez-Pop and Pierre Lestage and Laurence Danober and Kastrup, {Jette Sandholm Jensen} and Bernard Pirotte",

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doi = "10.1021/jm501268r",

language = "English",

volume = "57",

pages = "9539--53",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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T1 - 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-benzothiadiazine 1,1-Dioxides

AU - Francotte, Pierre

AU - Nørholm, Ann-Beth

AU - Deva, Taru

AU - Olsen, Lars

AU - Frydenvang, Karla

AU - Goffin, Eric

AU - Fraikin, Pierre

AU - de Tullio, Pascal

AU - Challal, Sylvie

AU - Thomas, Jean-Yves

AU - Iop, Fabrice

AU - Louis, Caroline

AU - Botez-Pop, Iuliana

AU - Lestage, Pierre

AU - Danober, Laurence

AU - Kastrup, Jette Sandholm Jensen

AU - Pirotte, Bernard

PY - 2014/11/26

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N2 - 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.

AB - 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.

KW - Allosteric Site

KW - Animals

KW - Benzothiadiazines

KW - Calorimetry

KW - Chemistry, Pharmaceutical

KW - Crystallography, X-Ray

KW - Cyclic S-Oxides

KW - Dimerization

KW - Drug Design

KW - Electrophysiology

KW - Hippocampus

KW - Humans

KW - Hydrogen

KW - Kinetics

KW - Mice

KW - Oxides

KW - Propionates

KW - Protein Binding

KW - Rats

KW - Rats, Wistar

KW - Receptors, AMPA

KW - Temperature

KW - Thermodynamics

KW - Thiadiazines

U2 - 10.1021/jm501268r

DO - 10.1021/jm501268r

M3 - Journal article

C2 - 25375781

SN - 0022-2623

VL - 57

SP - 9539

EP - 9553

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -