The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement |
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| Institution: | 1. Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;2. Pre-Pivotal Drug Product, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;3. Pharmicokinetics and Drug Metabolism, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;4. Neuroscience Research, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;5. Molecular Engineering, Amgen Discovery Research, Amgen Inc., Thousand Oaks, CA 91320, United States;1. Discovery Sciences and Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States;2. Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States;1. Division of Crop Foundation, National Institute of Crop Science (NICS), Rural Development Administration (RDA), Wanju 55365, Republic of Korea;2. Department of Crop Science and Biotechnology, Dankook University, Cheonan 31116, Republic of Korea;3. Department of Biological Sciences, Chonbuk National University, Jeonju 54896, Republic of Korea;4. Forest Biomaterials Research Center, National Institute of Forest Science (NIFS), Jinju 52817, Republic of Korea;1. China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China;2. School of Pharmacy, Tianjin Medical University, Tianjin 300070, China;3. Centre de recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France;1. Department of Chemistry, Prof John Barnabas Post Graduate School of Biological Studies, Ahmednagar College, Ahmednagar, Ahmednagar 414001, India;2. Department of Chemistry, Deogiri College, Station Road, Aurangabad 431 005, MS, India;3. Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, MS, India;4. Department of Pharmaceutical Chemistry, R C Patel Institute of Pharmaceutical Education & Research, Shirpur 425405, MS, India;5. Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431401, MS, India;6. Department of Animal Biology, University of Hyderabad, Hyderabad, 500046, India;1. Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, PR China;2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, PR China;3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China |
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| Abstract: | The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors. |
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| Keywords: | Bioisostere BACE1 |
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