Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology |
| |
| Institution: | 1. Center for Drug Discovery and Department of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02155, USA;2. Biotechnology Research and Training Center, University of North Carolina-Pembroke, Pembroke, NC 28372, USA;1. Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan;2. Pharmacovigilance, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan;1. Laboratory of Evolutionary Biology, Ecology and Management of Ecosystems, Faculty of Sciences and Techniques, Cheikh Anta Diop University of Dakar, Dakar, Senegal;2. CNRS – Università di Corsica, UMR 6134 – SPE, SERME Service d’Etude et de Recherche en Microscopie Electronique, 20250 Corte, Corsica, France;1. Department of Neuroscience, Psychology, Drug Research and Child''s Health - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino, FI, Italy;2. Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, via Orabona 4, 70125, Bari, Italy;3. Department of Oncology, University of Turin, Via Santena 5/bis, 10126, Torino, Italy;4. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100, Siena, Italy;5. Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017, Bobigny, France;1. 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, China;2. Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;3. Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;4. PKUCare Pharmaceutical R&D Center, Beijing 102206, China;1. Medical School of Kunming University of Science and Technology, Kunming, Yunnan 650500, China;2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;3. Faculty of Life Science and Technology of Kunming University of Science and Technology, Kunming, Yunnan 650500, China;1. Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden;2. The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden;3. Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory Drug Discovery and Development Platform, Department of Pharmacy, Uppsala University, BMC, Box 580, SE-751 23 Uppsala, Sweden;4. The Beijer Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden |
| |
| Abstract: | FAAH inhibitors offer safety advantages by augmenting the anandamide levels “on demand” to promote neuroprotective mechanisms without the adverse psychotropic effects usually seen with direct and chronic activation of the CB1 receptor. FAAH is an enzyme implicated in the hydrolysis of the endocannabinoid N-arachidonoylethanolamine (AEA), which is a partial agonist of the CB1 receptor. Herein, we report the discovery of a new series of highly potent and selective carbamate FAAH inhibitors and their evaluation for neuroprotection. The new inhibitors showed potent nanomolar inhibitory activity against human recombinant and purified rat FAAH, were selective (>1000-fold) against serine hydrolases MGL and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Evaluation of FAAH inhibitors 9 and 31 using the in vitro competitive activity-based protein profiling (ABPP) assay confirmed that both inhibitors were highly selective for FAAH in the brain, since none of the other FP-reactive serine hydrolases in this tissue were inhibited by these agents. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on known FAAH cocrystal structures. To rationally design new molecules that are irreversibly bound to FAAH, we have constructed “precovalent” FAAH-ligand complexes to identify good binding geometries of the ligands within the binding pocket of FAAH and then calculated covalent docking poses to select compounds for synthesis. FAAH inhibitors 9 and 31 were evaluated for neuroprotection in rat hippocampal slice cultures. In the brain tissue, both inhibitors displayed protection against synaptic deterioration produced by kainic acid-induced excitotoxicity. Thus, the resultant compounds produced through rational design are providing early leads for developing therapeutics against seizure-related damage associated with a variety of disorders. |
| |
| Keywords: | Fatty acid amide hydrolase (FAAH) FAAH inhibitor Monoacylglycerol lipase (MGL) Cannabinoid CB1 receptor Endocannabinoid system Hippocampus Neuroprotection |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
