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Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine

机译：通过3-α-氧杂氮杂环丁烷的生物等位修饰研究作为三重再摄取抑制剂的3-氨基氮杂环丁烷

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摘要

For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (>3) and Boc-protected 3-azetidinal (>9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound >10dl as a candidate for further studies.

机译：为了开发广谱抗抑郁药3-氨基氮杂环丁烷衍生物，对3-α-氧氮杂环丁烷进行生物等位修饰，探索了两种化合物。我们分别从Boc保护的3-azetidinone（> 3 ）和Boc保护的3-azetidinal（> 9 ）开始，在A和B系列中合成了166种新颖的3-氨基氮杂环丁烷衍生物。，通过并行综合。通过神经递质转运蛋白摄取测定试剂盒，使用分别分别转染了3种和3种类型的人胚肾293（HEK293）细胞的神经递质转运蛋白摄取测定试剂盒，测定了对血清素（5-HT），去甲肾上腺素（NE）和多巴胺（DA）神经递质的抑制再摄取活性。人类转运蛋白（hSERT，hNET和hDAT）。我们的研究旨在鉴定对hSERT> hNET> hDAT具有相对抑制活性的化合物。包括微粒体稳定性，CYP，hERG测定，Ames试验，BBB和PK研究在内的前导优化导致确定化合物> 10dl 作为进一步研究的候选对象。

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期刊名称 ACS Medicinal Chemistry Letters
作者
Minsoo Han; Chiman Song; Nakcheol Jeong; Hoh-Gyu Hahn; *;
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作者单位

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年(卷),期 2014(5),9
年度 2014
页码 999–1004
总页数 6
原文格式 PDF
正文语种
中图分类药物化学;
关键词
Depression triple reuptake inhibitor 3-aminoazetidines bioisosterism;

机译：抑郁症;三重再摄取抑制剂;3-氨基氮杂环丁烷;生物立体异构;

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专利

1. Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine [J] . Minsoo Han, Chiman Song, Nakcheol Jeong ACS medicinal chemistry letters . 2014,第9期

机译：通过3-α-氧杂氮杂环丁烷的生物等位修饰探索作为三重再摄取抑制剂的3-氨基氮杂环丁烷
2. Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS). [J] . Liang Y, Shaw AM, Boules M, The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics . 2008,第2期

机译：新型三重再摄取抑制剂（1S，2S）-3-（甲氨基）-2-（萘-2-基）-1-苯基丙烷-1-醇（PRC200-SS）的抗抑郁药理作用。
3. Structural Exploration of (3S,6S)-6-Benzhydryl-N- benzyItetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants [J] . Soumava Santra, Sanjib Gogoi, Bhaskar Gopishetty ChemMedChem . 2012,第12期

机译：（3S，6S）-6-苯甲基-N-苄基四氢-2H-吡喃-3-胺类似物的结构探索：潜在的三联单胺再摄取抑制剂作为潜在的抗抑郁药的鉴定。
4. SAR STUDY OF GLYCOGEN PHOSPHORYLASE INHIBITORS: HETEROCYCLES AS BIOISOSTERIC AMIDE REPLACEMENTS IN N-ACYL-β-D-GLUCOPYRANOSYLAMINES AND N-ACYL-N'-β-D-GLUCOPYRANOSYL UREAS [C] . Toth M., Varga G. T., Polyak M. International Carbohydrate Symposium . 2013

机译：SAR研究糖原磷酸化酶抑制剂：杂环作为N-酰基-β-D-吡喃葡萄糖胺和N-酰基-N'-β-D-吡喃葡萄糖脲替代的生物蛋白酶酰胺
5. Design synthesis and biological evaluation of bioisosteric analogues of dasatinib as Src, Abl and Abl T3151 protein tyrosine kinase inhibitors [D] . Patel, Jay P. 2013

机译：dasatinib作为Src，Abl和Abl T3151蛋白酪氨酸激酶抑制剂的生物立体异构体的设计合成和生物学评估
6. Structural Exploration of (3S6S)-6-Benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants [O] . Dr Soumava Santra, Dr Sanjib Gogoi, Dr Bhaskar Gopishetty, -1

机译：（3S6S）-6-苯甲酰基 - N-苄基四羟基-2H-吡喃-3-胺类似物的结构探测：鉴定有效三倍甘油再摄取抑制剂作为潜在的抗抑郁剂
7. Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of a-L-fucosidase [O] . Bathula, Chandramohan, Ghosh, Shreemoyee, Hati, Santanu, 2017

机译：已知岩藻糖苷酶抑制剂的生物等排修饰以发现新的α-L-岩藻糖苷酶抑制剂

Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine

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