Synthesis and Biological Evaluation of Five-Atom-Linker-Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile.,ChemMedChem

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Synthesis and Biological Evaluation of Five-Atom-Linker-Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-11-20 , DOI: 10.1002/cmdc.201900439
Chunhui Wu _{1,

2} , Yu Wang _{1,

3} , Feipu Yang ₃ , Wenqiang Shi ₃ , Zhen Wang ₃ , Ling He ₁ , Yang He ₃ , Jingshan Shen ₃

Affiliation

Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them, 7-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D2 R agonism, 5-HT1A R agonism, 5-HT2A R antagonism, and blockade of SERT activities, was found to decrease psychosis- and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.

中文翻译：

具有非典型抗精神病药物特征的五原子连接基芳基哌嗪衍生物的合成和生物学评估。

在这里，我们描述了一组潜在的广谱抗精神病药新的芳基哌嗪衍生物。总体结构包含喹啉酮样部分，芳基哌嗪部分和五原子接头。其中，7-（5-（4-（苯并[d]异噻唑-4-基）哌嗪-1-基）戊基）喹啉-2（1H）-1（S6）显示出良好的临床前概况。发现化合物S6具有部分D2 R激动作用，5-HT1A R激动作用，5-HT2A R拮抗作用和对SERT活性的阻断作用，可减轻啮齿动物的精神病和抑郁样症状。S6的多药理学特征可为治疗其他各种中枢神经系统疾病（如焦虑症，抑郁症和痴呆症相关的精神病）提供机会。此外，S6表现出可接受的安全性，毒理学和药代动力学特征，

更新日期：2019-11-20

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