Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines.,ACS Medicinal Chemistry Letters

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Discovery of VU6005649, a CNS Penetrant mGlu7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-09-01 , DOI: 10.1021/acsmedchemlett.7b00317
Masahito Abe _{1,

2} , Mabel Seto _{1,

2} , Rocco G Gogliotti _{1,

2} , Matthew T Loch _{1,

2} , Katrina A Bollinger ₂ , Sichen Chang ₂ , Eileen M Engelberg _{1,

2} , Vincent B Luscombe _{1,

2} , Joel M Harp ₃ , Michael Bubser _{1,

2} , Darren W Engers _{1,

2} , Carrie K Jones _{1,

2,

4} , Alice L Rodriguez _{1,

2} , Anna L Blobaum _{1,

2} , P Jeffrey Conn _{1,

2,

4} , Colleen M Niswender _{1,

2,

4} , Craig W Lindsley _{1,

2,

4}

Affiliation

Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

中文翻译：

发现VU6005649，这是CNS渗透性mGlu7 / 8受体PAM，它是从一系列吡唑并[1,5-a]嘧啶衍生而来的。

在这里，我们报告一系列基于具有出色的中枢神经系统渗透性（Kps> 1和Kp，uus> 1）的吡唑并[1,5-a]嘧啶核的mGlu7 PAM中的结构活性关系。该系列的类似物被证明具有III类mGlu受体选择性的范围，但是VU6005649作为第一个双重mGlu7 / 8 PAM出现，填补了III类mGlu受体PAM工具箱中的空白，并在小鼠上下文恐惧条件下证明了体内功效模型。

更新日期：2017-09-12

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