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
  • 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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