1. Academic Validation
  2. 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

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. 2021 Aug 12;64(15):11014-11044. doi: 10.1021/acs.jmedchem.1c00432.
Shuhei Ikeda 1 Hideyuki Sugiyama 1 Hidekazu Tokuhara 1 Masataka Murakami 1 Minoru Nakamura 1 Yuya Oguro 1 Jumpei Aida 1 Nao Morishita 1 Satoshi Sogabe 1 Douglas R Dougan 2 Sean C Gay 2 Ling Qin 2 Naoto Arimura 1 Yasuko Takahashi 1 Masako Sasaki 1 Yusuke Kamada 1 Kazunobu Aoyama 1 Kouya Kimoto 3 Makoto Kamata 1
Affiliations

Affiliations

  • 1 Research, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 2 Structural Biology and Biophysics, Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
  • 3 Pharmaceutical Sciences, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
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 (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.

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