Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors

Bioorg Med Chem. 2024 Sep 1:111:117844. doi: 10.1016/j.bmc.2024.117844. Epub 2024 Jul 23.

Abstract

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.

Keywords: Activity-based protein profiling; Anti-cancer agents; Inhibitor discovery; Monoacylglycerol lipase; Reversible inhibitors.

MeSH terms

  • Amides* / chemical synthesis
  • Amides* / chemistry
  • Amides* / pharmacology
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoacylglycerol Lipases* / antagonists & inhibitors
  • Monoacylglycerol Lipases* / metabolism
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Structure-Activity Relationship

Substances

  • Monoacylglycerol Lipases
  • Enzyme Inhibitors
  • Amides
  • Antineoplastic Agents
  • Naphthalenes