Design,synthesis and evaluation of pyrazolopyrimidinone derivatives as novel PDE9A inhibitors for treatment of Alzheimer’s disease |
| |
| Institution: | 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;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 and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand;2. Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand;3. Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand;4. The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, Thailand;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 |
| |
| Abstract: | Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer’s disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC50 of 2.0 nM against PDE9, showed good metabolic stability (t1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification. |
| |
| Keywords: | Phosphodiesterase-9 Alzheimer’s disease Molecular docking |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
