Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints |
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| Institution: | 1. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA;2. Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Biotechnology Center, San Diego, CA 92121, USA;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India;1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China;2. State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau, China;3. The Center for Disease Control and Prevention of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830002, China;4. Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA;5. Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford OX3 7LE, United Kingdom;6. Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China;1. Department of Pesticide Chemistry, College of Science, China Agricultural University, Beijing, China;2. State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection and Shenzhen Agricultural Genome Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China;1. Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA;2. Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA;3. Department of Chemistry, Stanford University, Stanford, CA 94305, USA;4. Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA;5. Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA;1. Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States;2. Center for Pulmonary Vascular Disease, Duke University Medical Center, Durham, NC 27710, United States;1. Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, United States;2. College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China;3. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China |
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| Abstract: | Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer’s disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described. |
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| Keywords: | BACE1 inhibitor Alzheimer’s disease Cyclopropyl Conformational constraint Structure-based drug design |
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