Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs
Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs
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DOI：
10.1021/acsmedchemlett.7b00249
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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：
--
作者：
Engers, Julie L.;Bollinger, Katrina A.;Lindsley, Craig W.
Herein, we detail the optimization of the mGlu(3) NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu(3) NAM scaffold that engenders potent and selective mGlu(3) inhibition (mGlu(3) IC50 = 245 nM, mGlu(2) IC50 > 30 mu M) with excellent central nervous system penetration (rat brain/plasma K-p = 1.2, K-p,K-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.).
