Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors
Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors
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DOI：
10.1016/j.bmc.2016.03.038
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发表时间：
2016-05-01
影响因子：
3.5
通讯作者：
Wanner, Klaus T.
中科院分区：
文献类型：
--
作者：
Hellenbrand, Tim;Hoefner, Georg;Wanner, Klaus T.
在这项研究中，我们公开了新的4-取代的哌啶甲酸衍生物的GABA转运mGAT 1的抑制剂的设计和合成。基于分子建模研究，假定化合物采用与有效mGAT 1抑制剂哌啶甲酸类似的结合姿势。由于在4-位的取代不应导致哌啶甲酸的能量上不利的取向，因为对于N-取代的衍生物是这种情况，因此预期这将导致高度有效的结合剂。为了合成新的4-取代的哌啶甲酸衍生物，采用线性合成策略。作为关键步骤，使用钯催化的交叉偶联反应将所需的联芳基部分连接到哌啶甲酸骨架的4位中不同长度的烯基或炔基间隔基的X位。对所得氨基酸的结合亲和力和对mGAT 1的抑制效力进行表征。尽管发现的生物活性通常不显著至较差，但可以鉴定出两种化合物，其中一种对mGAT 1（rac-57）具有合理的结合亲和力，另一种对mGAT 4（rac-84）具有显著的抑制效力，这两种化合物均显示出对单个转运蛋白的轻微亚型选择性。(C)2016爱思唯尔有限公司版权所有
In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the x-position of the alkenyl-or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified. (C) 2016 Elsevier Ltd. All rights reserved.