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

Eric Goffin; Thomas Drapier; Anja Probst Larsen; Pierre Geubelle; Christopher P Ptak; Saara Laulumaa; Karoline Rovinskaja; Julie Gilissen; Pascal de Tullio; Lars Olsen; Karla Frydenvang; Bernard Pirotte; Julien Hanson; Robert E Oswald; Jette Sandholm Kastrup; Pierre Francotte

doi:10.1021/acs.jmedchem.7b01323

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

Eric Goffin, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Pascal de Tullio, Lars Olsen, Karla Frydenvang, Bernard Pirotte, Julien Hanson, Robert E Oswald, Jette Sandholm Kastrup, Pierre Francotte

17 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	1
Pages (from-to)	251–264
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01323
Publication status	Published - 11 Jan 2018

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10.1021/acs.jmedchem.7b01323

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Goffin, E., Drapier, T., Larsen, A. P., Geubelle, P., Ptak, C. P., Laulumaa, S., Rovinskaja, K., Gilissen, J., Tullio, P. D., Olsen, L., Frydenvang, K., Pirotte, B., Hanson, J., Oswald, R. E., Kastrup, J. S., & Francotte, P. (2018). 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, 61(1), 251–264. https://doi.org/10.1021/acs.jmedchem.7b01323

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. / Goffin, Eric; Drapier, Thomas; Larsen, Anja Probst et al.

In: Journal of Medicinal Chemistry, Vol. 61, No. 1, 11.01.2018, p. 251–264.

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

Goffin, E, Drapier, T, Larsen, AP, Geubelle, P, Ptak, CP, Laulumaa, S, Rovinskaja, K, Gilissen, J, Tullio, PD, Olsen, L, Frydenvang, K, Pirotte, B, Hanson, J, Oswald, RE, Kastrup, JS & Francotte, P 2018, '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, vol. 61, no. 1, pp. 251–264. https://doi.org/10.1021/acs.jmedchem.7b01323

Goffin E, Drapier T, Larsen AP, Geubelle P, Ptak CP, Laulumaa S et al. 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. 2018 Jan 11;61(1): 251–264. doi: 10.1021/acs.jmedchem.7b01323

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title = "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",

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.",

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author = "Eric Goffin and Thomas Drapier and Larsen, {Anja Probst} and Pierre Geubelle and Ptak, {Christopher P} and Saara Laulumaa and Karoline Rovinskaja and Julie Gilissen and Tullio, {Pascal de} and Lars Olsen and Karla Frydenvang and Bernard Pirotte and Julien Hanson and Oswald, {Robert E} and Kastrup, {Jette Sandholm} and Pierre Francotte",

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T1 - 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

AU - Goffin, Eric

AU - Drapier, Thomas

AU - Larsen, Anja Probst

AU - Geubelle, Pierre

AU - Ptak, Christopher P

AU - Laulumaa, Saara

AU - Rovinskaja, Karoline

AU - Gilissen, Julie

AU - Tullio, Pascal de

AU - Olsen, Lars

AU - Frydenvang, Karla

AU - Pirotte, Bernard

AU - Hanson, Julien

AU - Oswald, Robert E

AU - Kastrup, Jette Sandholm

AU - Francotte, Pierre

PY - 2018/1/11

Y1 - 2018/1/11

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1021/acs.jmedchem.7b01323

DO - 10.1021/acs.jmedchem.7b01323

M3 - Journal article

C2 - 29256599

SN - 0022-2623

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SP - 251

EP - 264

JO - Journal of Medicinal Chemistry

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ER -

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

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