7L50

Crystal structure of human monoacylglycerol lipase in complex with compound 4f

7L50 の概要

• エントリーDOI: 10.2210/pdb7l50/pdb
• 分子名称: Monoglyceride lipase, ACETATE ION, (2s,4R)-2-{3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl}-7-oxa-5-azaspiro[3.4]octan-6-one, ... (4 entities in total)
• 機能のキーワード: inhibitor, serine hydrolase, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 142868.86

構造登録者

Qin, L.,Lane, W.,Skene, R.J. (登録日: 2020-12-21, 公開日: 2021-08-11, 最終更新日: 2023-10-18)

主引用文献

Ikeda, S.,Sugiyama, H.,Tokuhara, H.,Murakami, M.,Nakamura, M.,Oguro, Y.,Aida, J.,Morishita, N.,Sogabe, S.,Dougan, D.R.,Gay, S.C.,Qin, L.,Arimura, N.,Takahashi, Y.,Sasaki, M.,Kamada, Y.,Aoyama, K.,Kimoto, K.,Kamata, M.
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.
J.Med.Chem., 64:11014-11044, 2021

PubMed 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 and its co-crystal structure with MAGL, structure-based drug discovery (SBDD) approach enabled us to generate various spiro scaffolds like (azetidine-lactam), (cyclobutane-lactam), and (cyclobutane-carbamate) as novel bioisosteres of 3-oxo-3,4-dihydro-2-benzo[][1,4]oxazin-6-yl moiety in with higher lipophilic ligand efficiency (LLE). Optimization of the left hand side afforded as a promising reversible MAGL inhibitor, which showed potent in vitro MAGL inhibitory activity (IC 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.

PubMed: 34328319
DOI: 10.1021/acs.jmedchem.1c00432

実験手法

X-RAY DIFFRACTION (2.3 Å)