期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 20, 页码 14011-14028出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c01034
关键词
-
This study optimized the GPR139 agonist TAK-041 and synthesized new compounds, evaluating their activity at the GPR139 receptor. The compounds showed potential therapeutic effects on schizophrenia symptoms in murine models. Compound 20a exhibited the best activity and pharmacokinetic properties, making it a promising candidate as an antischizophrenia drug.
The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC50 = 31.4 nM) and 20a (EC50 = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据