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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-14 eCollection Date: 2025-05-08 DOI:10.1021/acsmedchemlett.5c00063

Joanna L Chen, Joey L Methot, Matthew J Mitcheltree, Andrew Musacchio, Emily B Corcoran, Guo Feng, Alfred Lammens, Klaus Maskos, Rachel L Palte, Meredith M Rickard, Karin M Otte, My S Mansueto, Sriraman Venkat, Christopher Sondey, Maren Thomsen, Charles A Lesburg, Xavier Fradera, Matthew J Fell, Erin F DiMauro, Phieng Siliphaivanh

引用次数: 0

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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桥接苯氮卓类酰胺作为RIPK1选择性变构调节剂的发现。

受体相互作用蛋白激酶1 （RIPK1）在坏死性坏死中起重要作用，坏死性坏死是一种炎性的、不依赖于caspase的程序性细胞死亡。RIPK1的变构抑制剂已被证明可以阻止坏死细胞死亡，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接苯氮卓酰胺的结构信息发现，作为我们开发具有低预期口服剂量的中枢神经系统渗透小分子RIPK1抑制剂的一部分。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.