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.

Eur J Med Chem

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:

Published: June 2015

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.

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http://dx.doi.org/10.1016/j.ejmech.2015.04.060DOI Listing

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