Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
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DOI：
10.1021/acsmedchemlett.7b00279
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发表时间：
2017-09-01
影响因子：
4.2
通讯作者：
Lindsley, Craig W.
中科院分区：
文献类型：
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作者：
Bollinger, Katrina A.;Felts, Andrew S.;Lindsley, Craig W.
在此，我们详细介绍了mGlu（2）负变构调节剂（NAM）VU 6001192的优化，通过还原方法提供了一种新的，简化的mGlu（2）NAM支架。这种新的化学型不仅提供有效的和选择性的mGlu（2）抑制，如VU 6001966（mGlu（2）IC 50 = 78 nM，mGlu（3）IC 50> 30 μ M）所示，而且还提供优异的中枢神经系统（CNS）渗透（K-p = 1.9，K-p，K-uu = 0.78），这是在所有先前公开的mGlu（2）NAM中缺乏的特征（K（p）s近似于0.3，K（p，uu）s近似于0.1）。此外，该系列基于整体性能，代表了潜在mGlu（2）PET示踪剂开发的令人兴奋的领先系列。
Herein, we detail the optimization of the mGlu(2) negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu(2) NAM scaffold. This new chemotype not only affords potent and selective mGlu(2) inhibition, as exemplified by VU6001966 (mGlu(2) IC50 = 78 nM, mGlu(3) IC50 > 30 mu M), but also excellent central nervous system (CNS) penetration (K-p = 1.9, K-p,K-uu = 0.78), a feature devoid in all previously disclosed mGlu(2) NAMs (K(p)s approximate to 0.3, K(p,uu)s approximate to 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu(2) PET tracer development.