Abstract
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 IC 50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC 50 = 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.
| Original language | English |
|---|---|
| Pages (from-to) | 629-637 |
| Number of pages | 9 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 85 |
| DOIs | |
| Publication status | Published - 2014 Oct 6 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
}
Novel thienopyrimidinones as mGluR1 antagonists. / Kim, Youngjae; Kim, Jeeyeon; Kim, Sora; Ki, Yooran; Seo, Seon Hee; Tae, Jinsung; Ko, Min Kyung; Jang, Hyun Seo; Lim, Eun Jeong; Song, Chiman; Cho, Yoonjeong; Koh, Hae Young; Chong, Youhoon; Choo, Il Han; Keum, Gyochang; Min, Sun Joon; Choo, Hyunah.
In: European Journal of Medicinal Chemistry, Vol. 85, 06.10.2014, p. 629-637.Research output: Contribution to journal › Article
TY - JOUR
T1 - Novel thienopyrimidinones as mGluR1 antagonists
AU - Kim, Youngjae
AU - Kim, Jeeyeon
AU - Kim, Sora
AU - Ki, Yooran
AU - Seo, Seon Hee
AU - Tae, Jinsung
AU - Ko, Min Kyung
AU - Jang, Hyun Seo
AU - Lim, Eun Jeong
AU - Song, Chiman
AU - Cho, Yoonjeong
AU - Koh, Hae Young
AU - Chong, Youhoon
AU - Choo, Il Han
AU - Keum, Gyochang
AU - Min, Sun Joon
AU - Choo, Hyunah
PY - 2014/10/6
Y1 - 2014/10/6
N2 - 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 IC 50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC 50 = 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.
AB - 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 IC 50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC 50 = 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.
UR - http://www.scopus.com/inward/record.url?scp=84906079450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906079450&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.08.027
DO - 10.1016/j.ejmech.2014.08.027
M3 - Article
VL - 85
SP - 629
EP - 637
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -