Novel thienopyrimidinones as mGluR1 antagonists
- Novel thienopyrimidinones as mGluR1 antagonists
- 김영재; 김지연; 김소라; 기유란; 서선희; 태진성; 고민경; 장현서; 임은정; 송치만; 조윤정; 고혜영; 정유훈; 추일한; 금교창; 민선준; 추현아
- mGluR1 antagonist; thienopyrimidinone; CNS disease; glutamate; metabotropic
- Issue Date
- European journal of medicinal chemistry
- VOL 85, 629-637
- There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50 = 9.87 μM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug–drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in in vitro and in vivo study for investigating CNS diseases.
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