Novel thienopyrimidinones as mGluR1 antagonists

• Discovery of novel thienopyrimidinones as mGluR1 antagonists.
• Potent inhibitory activity against mGluR1 (IC50 = 45 nM).
• Selectivities over mGluR5, hERG channel, and CYP isozymes.
• Good pharmacokinetic profile with moderate oral bioavailability.
• Broad use of the mGluR1 antagonist as a chemical probe.

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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