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.
Bibliographical noteFunding Information:
This research was supported by the Basic Science Research Program ( NRF-2013-R1A1A2A10009907 ) and the Priority Research Centers Program ( 2009-0093824 ) funded by the National Research Foundation of Korea (NRF) and a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea ( HI11C0998 ). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program ( 2E24510 and 2E24670 ).
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry