From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

From Hit to Lead: Structure-Based Optimization of Novel Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) for the Treatment of Inflammatory Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-30 , DOI: 10.1021/acs.jmedchem.3c02102
Liting Zhang ₁ , Yueshan Li _{1,

2} , Chenyu Tian ₁ , Ruicheng Yang ₁ , Yifei Wang ₁ , Haixing Xu ₁ , Qiucheng Zhu ₁ , Shasha Chen ₁ , Linli Li ₃ , Shengyong Yang _{1,

2}

Affiliation

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of cellular necroptosis, which is considered as an important therapeutic target for necroptosis-related indications. Herein, we report the structural optimization and structure–activity relationship investigations of a series of eutectic 5-substituted-indole-3-carboxamide derivatives. The prioritized compound 10b exhibited low nanomolar IC₅₀ values against RIPK1 and showed good kinase selectivity. Based on its eutectic structure, 10b occupied both the allosteric and ATP binding pockets of RIPK1, making it a potent dual-mode inhibitor of RIPK1. In vitro, 10b had a potent protective effect against necroptosis in cells. Compound 10b also provided robust protection in a TNFα-induced systemic inflammatory response syndrome (SIRS) model and imiquimod (IMQ)-induced psoriasis model. It also showed good pharmacokinetic properties and low toxicity. Overall, 10b is a promising lead compound for drug discovery targeting RIPK1 and warrants further study.

中文翻译：

从命中到先导：用于治疗炎症性疾病的受体相互作用蛋白激酶 1 (RIPK1) 新型选择性抑制剂的基于结构的优化

受体相互作用蛋白激酶1（RIPK1）是细胞坏死性凋亡的关键调节因子，被认为是坏死性凋亡相关适应症的重要治疗靶点。在此，我们报告了一系列共晶5-取代-吲哚-3-甲酰胺衍生物的结构优化和构效关系研究。优先化合物10b对 RIPK1 表现出低纳摩尔 IC ₅₀值，并表现出良好的激酶选择性。基于其共晶结构， 10b占据 RIPK1 的变构和 ATP 结合口袋，使其成为 RIPK1 的有效双模式抑制剂。在体外， 10b对细胞坏死性凋亡具有有效的保护作用。化合物10b还在 TNFα 诱导的全身炎症反应综合征 (SIRS) 模型和咪喹莫特 (IMQ) 诱导的银屑病模型中提供强大的保护。它还表现出良好的药代动力学特性和低毒性。总体而言， 10b是一种很有前景的先导化合物，可用于针对 RIPK1 的药物发现，值得进一步研究。

更新日期：2023-12-30

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南