Structure Report for: 7L4W

Qin, L.,Lane, W.,Skene, R.J.

Title: Design 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
Ikeda S, Sugiyama H, Tokuhara H, Murakami M, Nakamura M, Oguro Y, Aida J, Morishita N, Sogabe S and Kamata M <9 more author(s)> Ikeda S, Sugiyama H, Tokuhara H, Murakami M, Nakamura M, Oguro Y, Aida J, Morishita N, Sogabe S, Dougan DR, Gay SC, Qin L, Arimura N, Takahashi Y, Sasaki M, Kamada Y, Aoyama K, Kimoto K, Kamata M (- 9)
Ref: Journal of Medicinal Chemistry, :, 2021 : PubMed
Abstract


ESTHER: Ikeda_2021_J.Med.Chem__
PubMedSearch: Ikeda 2021 J.Med.Chem
PubMedID: 34328319
Gene_locus related to this paper: human-MGLL
Inhibitor(s) related to this paper: XP7-7L4U, SCHEMBL19421119, SCHEMBL19421059, SCHEMBL19834081

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 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 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.