Bioavailable pyrrolo-benzo-1,4-diazines as Nav1.7 sodium channel blockers for the treatment of pain |
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| Institution: | 1. Discovery Chemistry, Merck Research Laboratory, Kenilworth, NJ 07033, United States;2. Department of Medicinal Chemistry, Albany Molecular Research, Inc. (AMRI), Albany, NY 12203, United States;3. In Vivo Pharmacology Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;4. Cardiorenal Group, Merck Research Laboratory, Kenilworth, NJ 07033, United States;5. Neuroscience, Merck Research Laboratory, West Point, PA 19486, United States;6. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratory, Kenilworth, NJ 07033, United States;1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;2. Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;1. School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, PR China;2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, PR China;1. Department of Chemistry, Tsinghua University, Beijing 100084, China;2. Institute of Chemical Materials, CAEP, Mianyang 621900, China;1. Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;2. Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA;1. Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA;2. Cambria Pharmaceuticals, Cambridge, MA 02142, USA;3. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, USA;4. Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA |
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| Abstract: | A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure–activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 μM. |
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| Keywords: | Sodium channel Pain |
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