title: Novel thienopyrimidinones as mGluR1 antagonists.
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 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.
authors.affiliation: Center 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.
authors.forename: Youngjae
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center 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.
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Sora
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Yooran
authors.initials: Y
authors.lastname: Ki
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, South Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Tae
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Ko
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Hyun-Seo
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lim
authors.affiliation: Chemical Kinomics Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Chiman
authors.initials: C
authors.lastname: Song
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: YoonJeong
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Center for Neuroscience, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Koh
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Gwangjin-gu, Seoul 143-701, South Korea.
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.affiliation: School of Medicine, Chosun University, Dong-gu, Kwangju 501-759, South Korea.
authors.forename: Il Han
authors.initials: IH
authors.lastname: Choo
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea; Department of Biological Chemistry, University of Science and Technology, Youseong-gu, Daejeon 305-350, South Korea.
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, South Korea; Department of Biological Chemistry, University of Science and Technology, Youseong-gu, Daejeon 305-350, South Korea. Electronic address: hchoo@kist.re.kr.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D011744:Pyrimidinones; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1
keywords: CNS disease; Glutamate; Metabotropic; Thienopyrimidinone; mGluR1 antagonist