Ikeda, Shuhei published the artcileDesign and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl Moiety, Formula: C7H9NO4, the publication is Journal of Medicinal Chemistry (2021), 64(15), 11014-11044, database is CAplus and MEDLINE.
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 pharmacol. effect. Herein, we report the discovery of novel spiro chem. 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-2H-benzo[b][1,4]oxazin-6-yl moiety in 1 with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded 4f (I) as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC50 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.
Journal of Medicinal Chemistry published new progress about 2135785-62-3. 2135785-62-3 belongs to catalysis-chemistry, auxiliary class Oxazolidines, name is cis-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid, and the molecular formula is C7H9NO4, Formula: C7H9NO4.
Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia