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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 : 2017-08-18 00:00:00 , 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:

N-芳基苯氧基乙氧基吡啶酮类化合物的高选择性和CNS渗透性mGlu 3 NAM的设计与合成

本文中,我们通过还原论方法详细描述了mGlu 3 NAM,VU0650786的优化,以提供新颖,简化的mGlu 3 NAM支架,从而产生了有效且选择性的mGlu 3抑制作用(mGlu 3 IC 50 = 245 nM,mGlu 2 IC 50 > 30μM),具有出色的中枢神经系统穿透力(大鼠脑/血浆K p = 1.2,K p,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:2017-08-19
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