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
  • 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.
PMID: 34328319 DOI: 10.1021/acs.jmedchem.1c00432
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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