Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels |
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| Institution: | 1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan;2. Drug Discovery Research, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan;1. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden;2. Institute for Physiology, University of Münster and Hertie Research Group at Center for Physiology, University of Frankfurt, Germany;3. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden;1. Interdisciplinary Bioengineering Graduate Program, Georgia Institute of Technology, Atlanta, GA 30332, United States;2. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States;3. School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States;1. Lexington High School, 251 Waltham Street, Lexington, MA 02421, USA;2. Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore;1. Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;2. Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;3. Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA;4. Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA;5. Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France;6. Janssen Infectious Diseases BVBA, Beerse, Belgium |
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| Abstract: | N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain. |
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| Keywords: | N-type calcium channel Pain hERG |
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