Synthesis of macrocyclic α-ketoamide as a selective and reversible immunoproteasome inhibitor

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Abstract

In recent years, the human immunoproteasome has emerged as an attractive therapeutic target for various diseases, leading to a growing interest in the discovery of immunoproteasome inhibitors that selectively target specific subunits. Herein we report the design, synthesis, and evaluation of a new immunoproteasome inhibitor that feature a macrocyclic ring containing an internal α-ketoamide warhead. This compound is a selective and reversible inhibitor of immunoproteasome subunits β1i and β5i and shows essentially no inhibition of constitutive proteasome subunits. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)410-420
Number of pages11
JournalMedicinal Chemistry Research
Volume30
Issue number2
DOIs
StatePublished - Feb 2021

Bibliographical note

Funding Information:
This work was supported by the Center for Drug Design at the University of Minnesota. We thank Prof Rodney Johnson on the use of the ozone generator in his laboratory.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Keywords

  • Immunoproteasome
  • Immunoproteasome inhibitors
  • Ketoamide
  • Macrocyclic ketoamide
  • Reversible covalent inhibitors

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