Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China.
Department of Druggability Evaluation, Topharman Shanghai Co. Ltd., Shanghai, 201203, China.
ChemMedChem. 2019 Dec 17;14(24):2042-2051. doi: 10.1002/cmdc.201900439. Epub 2019 Nov 20.
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 D R agonism, 5-HT R agonism, 5-HT 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.
在此，我们描述了一组新的芳基哌嗪衍生物，它们可能是广谱抗精神病药。该类药物的一般结构包含喹啉酮类似物部分、芳基哌嗪部分和五原子连接体。其中，7-(5-(4-(苯并[d]异噻唑-4-基)哌嗪-1-基)戊基)喹啉-2(1H)-酮（S6）显示出有前景的临床前特征。化合物 S6 具有部分 D R 激动作用、5-HT R 激动作用、5-HT R 拮抗作用和 SERT 活性阻断作用，被发现可减少啮齿动物的精神病和抑郁样症状。S6 的多药理学特征为治疗各种其他中枢神经系统疾病（如焦虑、抑郁和与痴呆相关的精神病）提供了机会。此外，S6 表现出可接受的安全性、毒理学和药代动力学特征，已被选为进一步评估精神分裂症的临床前候选药物。
