Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.,ACS Medicinal Chemistry Letters

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Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-08-15 , DOI: 10.1021/acsmedchemlett.7b00249
Julie L Engers _{1,

2} , Katrina A Bollinger ₂ , Rebecca L Weiner ₂ , Alice L Rodriguez _{1,

2} , Madeline F Long ₂ , Megan M Breiner ₂ , Sichen Chang ₂ , Sean R Bollinger ₂ , Michael Bubser _{1,

2} , Carrie K Jones _{1,

2,

3} , Ryan D Morrison ₂ , Thomas M Bridges _{1,

2} , Anna L Blobaum _{1,

2} , Colleen M Niswender _{1,

2,

3} , P Jeffrey Conn _{1,

2,

3} , Kyle A Emmitte _{1,

2} , Craig W Lindsley _{1,

2}

Affiliation

Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

中文翻译：

高选择性和CNS渗透性mGlu3 NAM的N-芳基苯氧基乙氧基吡啶酮的设计与合成。

本文中，我们详细介绍了通过还原论方法对mGlu3 NAM（VU0650786）进行的优化，以提供新颖，简化的mGlu3 NAM支架，该支架可产生有效的选择性mGlu3抑制（mGlu3 IC50 = 245 nM，mGlu2 IC50> 30μM）。系统渗透（大鼠脑/血浆Kp = 1.2，Kp，uu = 0.40）。此外，这种新的化学型以VU6010572为例，仅需四个合成步骤，并在小鼠尾部悬浮液试验（MED = 3 mg / kg ip）中显示出改善的理化特性和体内功效。

更新日期：2017-08-18

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