Synthesis and Biological Evaluation of FiveāAtomāLinkerāBased Arylpiperazine Derivatives with an Atypical Antipsychotic Profile
Journal
ChemMedChem
Author(s)
Year
2019
Herein we describe a focused set of new arylpiperazine derivatives as potential broadāspectrum antipsychotics. The general structure contains a quinolinoneālike moiety, an arylpiperazine moiety, and a fiveāatom linker. Among them, 7ā(5ā(4ā(benzo[d]isothiazolā4āyl)piperazinā1āyl)pentyl)quinolinā2(1H)āone (S6) shows a promising preclinical profile. CompoundĀ S6, characterized by partial D2R agonism, 5āHT1AR agonism, 5āHT2AR antagonism, and blockade of SERT activities, was found to decrease psychosisā and depressiveālike symptoms in rodents. The polypharmacological profile ofĀ S6Ā could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore,Ā S6Ā demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.