Design and Synthesis of Novel Spiro Derivatives as Potent and Reversible Monoacylglycerol Lipase (MAGL) Inhibitors: Bioisosteric Transformation from 3-Oxo-3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazin-6-yl Moiety

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 <b>1</b> and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like <b>2a</b> (azetidine-lactam), <b>2b</b> (cyclobutane-lactam), and <b>2d</b> (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2<i>H</i>-benzo[<i>b</i>][1,4]oxazin-6-yl moiety in <b>1</b> with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded <b>4f</b> 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.