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Design and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl Moiety.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Aug 12; Vol. 64 (15), pp. 11014-11044. Date of Electronic Publication: 2021 Jul 30. - Publication Year :
- 2021
-
Abstract
- The therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors in central nervous system-related diseases has attracted attention worldwide. However, the availability of reversible-type inhibitor is still limited to clarify the pharmacological effect. Herein, we report the discovery of novel spiro chemical series as potent and reversible MAGL inhibitors with a different binding mode to MAGL using Arg57 and His121. Starting from hit compound 1 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like 2a (azetidine-lactam), 2b (cyclobutane-lactam), and 2d (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2 H -benzo[ b ][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC <subscript>50</subscript> 6.2 nM), good oral absorption, blood-brain barrier penetration, and significant pharmacodynamic changes (2-arachidonoylglycerol increase and arachidonic acid decrease) at 0.3-10 mg/kg, po. in mice.
- Subjects :
- Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Humans
Models, Molecular
Molecular Structure
Monoacylglycerol Lipases metabolism
Oxazines chemistry
Spiro Compounds chemical synthesis
Spiro Compounds chemistry
Structure-Activity Relationship
Drug Design
Enzyme Inhibitors pharmacology
Monoacylglycerol Lipases antagonists & inhibitors
Oxazines pharmacology
Spiro Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34328319
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00432