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Novel thienopyrimidinones as mGluR1 antagonists
Youngjae Kim1, Jeeyeon Kim1, Sora Kim2
1Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea; Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, South Korea.
European Journal of Medicinal Chemistry
|August 16, 2014
Summary
Researchers developed novel thienopyrimidinone derivatives as potent mGluR1 antagonists for central nervous system diseases. Compound 30 demonstrated significant inhibitory activity and favorable pharmacokinetic properties, making it a promising chemical probe.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Drug Discovery
Background:
- Metabotropic glutamate receptor 1 (mGluR1) antagonists are sought for central nervous system (CNS) disorders like seizures and neuropathic pain.
- Thienopyrimidinone derivatives represent a potential class of compounds for targeting mGluR1.
Purpose of the Study:
- To design, synthesize, and evaluate thienopyrimidinone derivatives as selective mGluR1 antagonists.
- To identify a potent and safe mGluR1 antagonist for further research in CNS diseases.
Main Methods:
- Synthesis of novel thienopyrimidinone derivatives.
- In vitro biological evaluation of inhibitory activity against mGluR1.
- Assessment of selectivity over mGluR5.
- Evaluation of hERG channel activity and CYP isozyme interactions.
- Pharmacokinetic profiling.
Main Results:
- Compound 30, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one, showed potent mGluR1 inhibition (IC50 = 45 nM) with good selectivity over mGluR5.
- Compound 30 exhibited marginal hERG channel activity (IC50 = 9.87 μM) and favorable CYP isozyme profiles.
- A good pharmacokinetic profile was observed for compound 30.
Conclusions:
- Compound 30 is a selective mGluR1 antagonist with promising pharmacokinetic properties.
- Compound 30 is likely devoid of cardiac side effects and drug-drug interactions.
- Compound 30 is a valuable chemical probe for in vitro and in vivo studies of CNS diseases.
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