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Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00279
Katrina A. Bollinger 1 , Andrew S. Felts 1, 2 , Christopher J. Brassard 1, 2 , Julie L. Engers 1, 2 , Alice L. Rodriguez 1, 2 , Rebecca L. Weiner 1 , Hyekyung P. Cho 1, 2 , Sichen Chang 1 , Michael Bubser 1, 2 , Carrie K. Jones 1, 2, 3 , Anna L. Blobaum 1, 2 , Colleen M. Niswender 1, 2, 3 , P. Jeffrey Conn 1, 2, 3 , Kyle A. Emmitte 1, 2, 4 , Craig W. Lindsley 1, 2, 4
Affiliation  

Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.

中文翻译:

基于截短的吡啶甲酰胺核的具有增强的效力和CNS穿透力的mGlu 2 NAM的设计与合成

在这里,我们详细介绍了通过还原论方法对mGlu 2负变构调节剂(NAM)VU6001192的优化,以提供新颖,简化的mGlu 2 NAM支架。这种新的化学型不仅可提供有效的选择性mGlu 2抑制作用(如VU6001966所示(mGlu 2 IC 50 = 78 nM,mGlu 3 IC 50 > 30μM ),而且还具有出色的中枢神经系统(CNS)渗透性(K p = 1.9) ,K p,uu = 0.78),这是在所有先前公开的mGlu 2 NAM中都没有的特征(K p s≈0.3 ,K p,uus≈0.1)。此外,基于总体性能,该系列代表了潜在的mGlu 2 PET示踪剂开发的激动人心的铅系列。
更新日期:2017-08-19
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