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Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile
Author(s) -
Wu Chunhui,
Wang Yu,
Yang Feipu,
Shi Wenqiang,
Wang Zhen,
He Ling,
He Yang,
Shen Jingshan
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900439
Subject(s) - moiety , linker , chemistry , psychosis , antipsychotic , pharmacology , anxiety , dementia , schizophrenia (object oriented programming) , stereochemistry , psychology , psychiatry , medicine , disease , computer science , operating system
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(1 H )‐one ( S6 ) shows a promising preclinical profile. Compound S6 , characterized by partial D 2 R agonism, 5‐HT 1A R agonism, 5‐HT 2A 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.