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 was written by Ikeda, Shuhei;Sugiyama, Hideyuki;Tokuhara, Hidekazu;Murakami, Masataka;Nakamura, Minoru;Oguro, Yuya;Aida, Jumpei;Morishita, Nao;Sogabe, Satoshi;Dougan, Douglas R.;Gay, Sean C.;Qin, Ling;Arimura, Naoto;Takahashi, Yasuko;Sasaki, Masako;Kamada, Yusuke;Aoyama, Kazunobu;Kimoto, Kouya;Kamata, Makoto. And the article was included in Journal of Medicinal Chemistry in 2021.Application of 142253-56-3 This article mentions the following:
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 pharmacol. effect. Herein, we report the discovery of novel spiro chem. 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 (I) 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. In the experiment, the researchers used many compounds, for example, 1-Boc-Azetidine-3-yl-methanol (cas: 142253-56-3Application of 142253-56-3).
1-Boc-Azetidine-3-yl-methanol (cas: 142253-56-3) belongs to alcohols. The oxygen atom of the strongly polarized O―H bond of an alcohol pulls electron density away from the hydrogen atom. This polarized hydrogen, which bears a partial positive charge, can form a hydrogen bond with a pair of nonbonding electrons on another oxygen atom. Alcohols may be oxidized to give ketones, aldehydes, and carboxylic acids. These functional groups are useful for further reactions. Oxidation of organic compounds generally increases the number of bonds from carbon to oxygen (or another electronegative element, such as a halogen), and it may decrease the number of bonds to hydrogen.Application of 142253-56-3
Referemce:
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