Open AccessDesign 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
Author(s) -
Shuhei Ikeda,
Hideyuki Sugiyama,
Hidekazu Tokuhara,
Masataka Murakami,
Masaru Nakamura,
Yuya Oguro,
Jumpei Aida,
Nao Morishita,
Satoshi Sogabe,
D.R. Dougan,
Ling Qin,
Naoto Arimura,
Yasuko Takahashi,
Masako Sasaki,
Yusuke Kamada,
Kazunobu Aoyama,
Kouya Kimoto,
Masakazu Kamata
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00432
Subject(s) - monoacylglycerol lipase , chemistry , moiety , stereochemistry , ic50 , combinatorial chemistry , pharmacology , biochemistry , in vitro , receptor , endocannabinoid system , medicine
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 50 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.