2. Academic Validation
  3. The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1

The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1

  • ACS Med Chem Lett. 2025 Apr 14;16(5):811-818. doi: 10.1021/acsmedchemlett.5c00063.
Joanna L Chen 1,  Joey L Methot 1,  Matthew J Mitcheltree 1,  Andrew Musacchio 1,  Emily B Corcoran 2,  Guo Feng 3,  Alfred Lammens 4,  Klaus Maskos 4,  Rachel L Palte 5,  Meredith M Rickard 1,  Karin M Otte 6,  My S Mansueto 3,  Sriraman Venkat 3,  Christopher Sondey 3,  Maren Thomsen 4,  Charles A Lesburg 5,  Xavier Fradera 1,  Matthew J Fell 3,  Erin F DiMauro 1,  Phieng Siliphaivanh 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 2 Department of Process Research and Development, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 3 Department of Discovery Quantitative Biosciences, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 4 Department of Protein Crystallography, Proteros Biostructures GmbH, Planegg-Martinsried, Bavaria 82152, Germany.
  • 5 Department of Structural Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 6 Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
PMID: 40365380 DOI: 10.1021/acsmedchemlett.5c00063
Abstract

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in Necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.

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