桥连苯并氮杂卓酰胺作为RIPK1选择性变构调节剂的发现
The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1.
作者信息
Chen Joanna L, Methot Joey L, Mitcheltree Matthew J, Musacchio Andrew, Corcoran Emily B, Feng Guo, Lammens Alfred, Maskos Klaus, Palte Rachel L, Rickard Meredith M, Otte Karin M, Mansueto My S, Venkat Sriraman, Sondey Christopher, Thomsen Maren, Lesburg Charles A, Fradera Xavier, Fell Matthew J, DiMauro Erin F, Siliphaivanh Phieng
机构信息
Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
Department of Process Research and Development, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
出版信息
ACS Med Chem Lett. 2025 Apr 14;16(5):811-818. doi: 10.1021/acsmedchemlett.5c00063. eCollection 2025 May 8.
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.
受体相互作用蛋白激酶1（RIPK1）在坏死性凋亡中起关键作用，坏死性凋亡是一种炎症性、不依赖半胱天冬酶的程序性细胞死亡形式。RIPK1的变构抑制剂已被证明可阻断坏死性凋亡细胞死亡，因此可能为一系列感染性、自身免疫性和神经退行性疾病提供潜在的治疗机会。我们报告了一系列新型桥连苯并氮杂卓酰胺的基于结构的发现，这是我们开发一种具有低预计口服人体剂量的可穿透中枢神经系统的RIPK1小分子抑制剂的努力的一部分。
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