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Discovery of 6,7-Dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives as mGluR2 Negative Allosteric Modulators with In Vivo Activity in a Rodent’s Model of Cognition
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c01227 Sergio A Alonso de Diego 1 , María Lourdes Linares 1 , Aránzazu García Molina 1 , Ana Isabel de Lucas 1 , Alcira Del Cerro 1 , Jose Manuel Alonso 1 , Luc Ver Donck 2 , Jose María Cid 1 , Andrés A Trabanco 1 , Michiel Van Gool 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c01227 Sergio A Alonso de Diego 1 , María Lourdes Linares 1 , Aránzazu García Molina 1 , Ana Isabel de Lucas 1 , Alcira Del Cerro 1 , Jose Manuel Alonso 1 , Luc Ver Donck 2 , Jose María Cid 1 , Andrés A Trabanco 1 , Michiel Van Gool 1
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Allosteric modulators of the metabotropic group II receptors, mGluR2 and mGluR3, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR2 negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR2 NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK–PD) relationship built showed that compound 11 occupied the mGluR2 receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.
中文翻译：
发现 6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-one 衍生物作为 mGluR2 负变构调节剂，在啮齿动物认知模型中具有体内活性
代谢型 II 类受体的变构调节剂 mGluR 2和 mGluR 3因其在情绪障碍中调节认知和神经功能的能力而被广泛探索，尽管尚未获得批准。在我们寻找新的选择性 mGluR 2负变构调节剂 (NAM) 的过程中，从我们发表的 1,3 系列中鉴定出一系列 6,7-二氢吡唑并[1,5- a ]pyrazin-4(5 H )-one 衍生物,5-三取代吡唑。初始命中的 SAR 演变导致 mGluR 2 NAM 效力提高 100 倍，并随后根据化合物11的总体特征（包括选择性和 ADMET 特性）进行选择。进一步建立的药代动力学-药效（PK-PD）关系表明，化合物11以剂量依赖性方式占据 mGluR 2受体。此外，该化合物在剂量为 0.32 mg/kg 的 V 迷宫中显示出体内活性，作为认知模型。选择化合物11进行进一步评估。
更新日期：2024-08-29
中文翻译：
发现 6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-one 衍生物作为 mGluR2 负变构调节剂，在啮齿动物认知模型中具有体内活性
代谢型 II 类受体的变构调节剂 mGluR 2和 mGluR 3因其在情绪障碍中调节认知和神经功能的能力而被广泛探索，尽管尚未获得批准。在我们寻找新的选择性 mGluR 2负变构调节剂 (NAM) 的过程中，从我们发表的 1,3 系列中鉴定出一系列 6,7-二氢吡唑并[1,5- a ]pyrazin-4(5 H )-one 衍生物,5-三取代吡唑。初始命中的 SAR 演变导致 mGluR 2 NAM 效力提高 100 倍，并随后根据化合物11的总体特征（包括选择性和 ADMET 特性）进行选择。进一步建立的药代动力学-药效（PK-PD）关系表明，化合物11以剂量依赖性方式占据 mGluR 2受体。此外，该化合物在剂量为 0.32 mg/kg 的 V 迷宫中显示出体内活性，作为认知模型。选择化合物11进行进一步评估。
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