Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1
Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1
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DOI：
10.1021/acs.jmedchem.6b00914
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发表时间：
2016-09-22
影响因子：
7.3
通讯作者：
Mhyre, Andrew J.
中科院分区：
文献类型：
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作者：
Cioffi, Christopher L.;Liu, Shuang;Mhyre, Andrew J.
我们之前披露了合理设计的N-（（1-（4-（丙基磺酰基）哌嗪-1-基）环烷基）甲基）苯甲酰胺甘氨酸转运蛋白-1 （GlyT-1）抑制剂的发现，以类似物10和11为代表。我们在此通过优化策略进一步描述了该系列的结构-活性关系探索，该优化策略主要集中在支架的磺胺和苯酰胺附件上。这些努力导致鉴定出具有良好的体外GlyT-1效力和选择性，有利的ADME和体外药理学特征，以及合适的药代动力学和安全性特征的先进导联。代表性的类似物(+)-67在啮齿类动物和非人灵长类动物的脑脊液甘氨酸生物标志物模型中表现出强大的体内活性。此外，啮齿动物微透析实验也表明，口服(+)-67显著提高内侧前额叶皮层（mPFC）内的细胞外甘氨酸水平。
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).