title: Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain.
abstract: Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Chemistry, College of Natural Sciences, Sangmyung University, Hong-ji moon 2-gil 20, Jongno-gu, Seoul 110-743, Republic of Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: Nam
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejon 305-350, Republic of Korea.
authors.forename: TaeHun
authors.initials: T
authors.lastname: Kim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Chemistry, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Jinsook
authors.initials: J
authors.lastname: Kwak
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Ko
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lim
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.affiliation: Department of Chemistry, College of Natural Sciences, Sangmyung University, Hong-ji moon 2-gil 20, Jongno-gu, Seoul 110-743, Republic of Korea.
authors.forename: Du-Jong
authors.initials: DJ
authors.lastname: Baek
authors.affiliation: Department of Global Medical Science, Sungshin University, Seoul 142-732, Republic of Korea. Electronic address: jlee@sungshin.ac.kr.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Biological Chemistry, Korea University of Science and Technology, Yuseong-Gu, Daejon 305-350, Republic of Korea. Electronic address: anpae@kist.re.kr.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy*; D009570:Nitriles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C000605575:2-(benzylamino)-6-(3-methyl-1H-pyrazole-5-carbonyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile; C000605574:2-(benzylamino)-6-(4-fluorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine-3-carbonitrile; D000700:Analgesics; D009570:Nitriles; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C023666:pyridine
keywords: Metabotropic glutamate receptor; Neuropathic pain; Thiophene derivatives; mGluR1 antagonist