Discovery of Aryl Formyl Piperidine Derivatives as Potent, Reversible, and Selective Monoacylglycerol Lipase Inhibitors
| Autor: | Zhong Liu, Qingjing Hao, Gui-min Zhang, Jinxin Wang, Yanguo Shang, Jing-chun Yao, Wenting Zhang, Jie Li, Zhi Zhuo'er, Yu-shan Ren |
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| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Cell Survival Drug Evaluation Preclinical Cell Line chemistry.chemical_compound Mice Structure-Activity Relationship Piperidines In vivo Drug Discovery medicine Structure–activity relationship Animals Humans Enzyme Inhibitors IC50 Binding Sites In vitro Monoacylglycerol Lipases Protein Structure Tertiary Rats Monoacylglycerol lipase Molecular Docking Simulation Kinetics Mechanism of action chemistry Docking (molecular) Drug Design Microsomes Liver Molecular Medicine Piperidine medicine.symptom Half-Life |
| Zdroj: | Journal of medicinal chemistry. 63(11) |
| ISSN: | 1520-4804 |
| Popis: | Most of the current monoacylglycerol lipase (MAGL) inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM). Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic subpocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression. |
| Databáze: | OpenAIRE |
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