Discovery of N-sulfonyl-7-azaindoline derivatives as potent,orally available and selective M4 muscarinic acetylcholine receptor agonists |
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| Affiliation: | 1. Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan;2. Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan;1. AskAt Inc., 4F Ito Bldg., 4-11-28 Meieki Nakamura-ku, Nagoya 450-0002, Japan;2. Discovery Research, RaQualia Pharma Inc, 8F Daiwa Meieki Bldg., 1-21-19 Meieki Minami, Nakamura-ku, Nagoya 450-0003, Japan;3. INC Research, 16F Shinagawa East One Tower, 2-16-1 Konan, Minato-ku, Tokyo 108-0075, Japan;4. Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan;1. Fundación Ciencia & Vida, Ñuñoa, Santiago 7780272, Chile;2. Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago 8370146, Chile;3. Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain;4. Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain;5. IdiSNA, Navarra Institute for Health Research, Pamplona, 31008, Spain;6. Department of Molecular Genetics and Microbiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O''Higgins 340, Santiago, Chile;7. Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona 08028, Spain;8. CIBERNED. Centro de Investigación en Red. Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28049, Madrid, Spain;1. Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;2. Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;3. Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;1. Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;2. Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;3. Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India;1. AstraZeneca R&D Boston, Oncology iMED, 35 Gatehouse Drive, Waltham, MA 02451, USA;2. AstraZeneca R&D Boston, Global Safety Assessment, 35 Gatehouse Drive, Waltham, MA 02451, USA;1. Mitobridge, Inc., 1030 Massachusetts Ave., Cambridge, MA 02138, United States;2. Aurigene Discovery Technologies, Ltd., Bengaluru, Karnataka, India;3. Astellas Pharma, Tsukuba, Japan |
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| Abstract: | We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1–10 mg/kg, po). |
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| Keywords: | Muscarinic acetylcholine receptor agonist Subtype-selective agonist Schizophrenia |
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