The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1
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.
Authors
- R.L. Palte (ORCID: https://orcid.org/0000-0001-6146-0551)
- Erin F. DiMauro (ORCID: https://orcid.org/0009-0009-5054-1140)
- Charles A. Lesburg (ORCID: https://orcid.org/0000-0001-7245-7331)
- Emily B. Corcoran (ORCID: https://orcid.org/0000-0002-9392-6923)
- Matthew J. Mitcheltree (ORCID: https://orcid.org/0000-0003-3774-628X)
- S. Venkat
- Phieng Siliphaivanh
- Maren Thomsen (ORCID: https://orcid.org/0000-0003-2561-7595)
- Alfred Lammens
- Christopher Sondey (ORCID: https://orcid.org/0000-0003-4855-8524)
- Karin M. Otte
- Xavier Fradera (ORCID: https://orcid.org/0000-0002-6118-075X)
- Joey L. Methot (ORCID: https://orcid.org/0000-0003-3374-181X)
- Joanna L. Chen
- K. Maskos
- Meredith M. Rickard (ORCID: https://orcid.org/0000-0002-4571-9743)
- My Sam Mansueto (ORCID: https://orcid.org/0000-0001-8633-2556)
- Andrew J. Musacchio (ORCID: https://orcid.org/0000-0002-8110-3540)
- Guo Feng (ORCID: https://orcid.org/0000-0002-6889-3998)
- Matthew Fell (ORCID: https://orcid.org/0000-0002-7776-2877)
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- ProterixBio (United States) (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00063
- Citations
- 1
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 0.94