7L4T

Crystal structure of human monoacylglycerol lipase in complex with compound 1

Summary for 7L4T

• Entry DOI: 10.2210/pdb7l4t/pdb
• Descriptor: Monoglyceride lipase, 6-{4-[(2-chloro-4-fluorophenoxy)methyl]piperidine-1-carbonyl}-2H-1,4-benzoxazin-3(4H)-one, ACETATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, serine hydrolase, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 71478.24

Authors

Qin, L.,Gay, S.C.,Lane, W.,Skene, R.J. (deposition date: 2020-12-21, release date: 2021-08-11, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)