Discovery of 4-substituted-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with improved metabolic stability
Discovery of 4-substituted-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with improved metabolic stability
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DOI：
10.1016/j.bmcl.2006.05.058
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发表时间：
2006-08-15
影响因子：
2.7
通讯作者：
Zimmerli, Daniel
中科院分区：
文献类型：
--
作者：
Alberati, Daniela;Hainzl, Dominik;Zimmerli, Daniel
一类新型的4-芳基-8-（2-羟基-2-苯基-环己基）-2,8-二氮杂螺[4.5]癸烷-1已被发现并开发为有效的选择性GlyT1抑制剂。这些分子在GlyT2亚型上缺乏活性，并且对μ -阿片受体以及NOP受体表现出极好的选择性。特别是这些新化合物4以及4-取代-8-（2-苯基-环己基）-2,8-diaza-spiro[4.5]decan-1-one 3与之前的三氮匹罗哌啶系列1和2相比，在啮齿动物中表现出更好的代谢稳定性和药代动力学特征。我们还在这些重氮匹罗哌啶系列中发现了降低哌啶氮碱度和降低hERG亲和力之间的关键关系。(c) 2006 Elsevier Ltd.版权所有。
A novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor. In particular these novel compounds 4 as well as the 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one 3 show improved metabolic stability and pharmacokinetic profiles in rodents compared to previous triazaspiropiperidine series 1 and 2. We have also identified within these diazaspiropiperidine series a key relationship between reducing basicity of the piperidine nitrogen and reducing hERG affinity. (c) 2006 Elsevier Ltd. All rights reserved.