Novel thienopyrimidinones as mGluR1 antagonists

Youngjae Kim, Jeeyeon Kim, Sora Kim, Yooran Ki, Seon Hee Seo, Jinsung Tae, Min Kyung Ko, Hyun Seo Jang, Eun Jeong Lim, Chiman Song, Yoonjeong Cho, Hae Young Koh, Youhoon Chong, Il Han Choo, Gyochang Keum, Sun Joon Min, Hyunah Choo

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 languageEnglish
Pages (from-to)629-637
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume85
DOIs
Publication statusPublished - 2014 Oct 6

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Pharmacokinetics
Central Nervous System Diseases
Drug interactions
Neurology
Neuralgia
Drug-Related Side Effects and Adverse Reactions
Drug Interactions
Isoenzymes
Seizures
metabotropic glutamate receptor type 1
Derivatives
Pharmaceutical Preparations
compound 30
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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. / Novel thienopyrimidinones as mGluR1 antagonists. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 85. pp. 629-637.
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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.",
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Kim, Y, Kim, J, Kim, S, Ki, Y, Seo, SH, Tae, J, Ko, MK, Jang, HS, Lim, EJ, Song, C, Cho, Y, Koh, HY, Chong, Y, Choo, IH, Keum, G, Min, SJ & Choo, H 2014, 'Novel thienopyrimidinones as mGluR1 antagonists', European Journal of Medicinal Chemistry, vol. 85, pp. 629-637. https://doi.org/10.1016/j.ejmech.2014.08.027

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 journalArticle

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.

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M3 - Article

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

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