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

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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 ( IF 6.8 ) Pub Date : 2017-12-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01323
Eric Goffin ₁ , Thomas Drapier ₁ , Anja Probst Larsen ₂ , Pierre Geubelle _{1,

3} , Christopher P. Ptak ₄ , Saara Laulumaa ₂ , Karoline Rovinskaja ₂ , Julie Gilissen _{1,

3} , Pascal de Tullio ₁ , Lars Olsen ₂ , Karla Frydenvang ₂ , Bernard Pirotte ₁ , Julien Hanson _{1,

3} , Robert E. Oswald ₄ , Jette Sandholm Kastrup ₂ , Pierre Francotte ₁

Affiliation

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.

中文翻译：

7-苯氧基取代的3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物作为α-氨基-3-羟基-5-羟基-4-甲基-4-异恶唑丙酸（AMPA）的正变构调节剂具有纳摩尔效价的受体

我们在这里报告7-苯氧基取代的3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物的合成及其作为AMPA受体阳性变构调节剂（AMPApams）的评估。考察了取代对苯氧基和4-位氮原子的影响。在HEK293细胞中表达的GluA2（Q）处（钙通量实验），最有效的化合物是11m（4-环丙基-7-（3-甲氧基苯氧基）-3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物，EC ₅₀= 2.0 nM）。使用隔离的GluA2配体结合结构域（GluA2-LBD）进行的小角X射线散射（SAXS）实验中的筛选中的Hill系数和二聚化曲线的形状与每个二聚体界面结合一个11m的分子是一致的，与迄今为止开发的大多数苯并噻二嗪二氧化物相反。通过与GluA2-LBD结合的11m的X射线结构和NMR证实了该观察结果。这是第一个达到纳摩尔范围的二氧化苯并噻二嗪二甲酰胺。

更新日期：2017-12-19

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