New Potent RIPK2 Inhibitors as a Promising Therapeutic Avenue for Colitis Through the Blockade of NOD Inflammatory Pathways,Journal of Medicinal Chemistry

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New Potent RIPK2 Inhibitors as a Promising Therapeutic Avenue for Colitis Through the Blockade of NOD Inflammatory Pathways
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-27 , DOI: 10.1021/acs.jmedchem.4c01313
Morgane Rivoal ₁ , Amélie Barzyck ₁ , Perrine Six ₁ , Xavier Dezitter ₁ , Min-Jeong Cornu-Choi ₁ , Mathilde Body-Malapel ₁ , Madjid Djouina ₁ , Christophe Waxin ₁ , Laurent Dubuquoy ₁ , Régis Millet ₁ , Natascha Leleu-Chavain ₁

Affiliation

Inflammatory bowel diseases (IBDs) are conditions characterized by chronic inflammation of the bowel. Receptor-interacting Ser/Thr protein kinase 2, a key mediator in nucleotide oligomerization domain (NOD)-like receptor (NLRs) 1 (NOD1) and NOD2 inflammatory pathways, has been shown to be involved in the development of these pathologies. Here, we report the development of a series of quinazolines as receptor-interacting serine/threonine protein kinase 2 (RIPK2) inhibitors most of which highly block the NOD1 pathway while others block both NOD pathways. Nine of our best compounds show high cellular engagement of RIPK2 and were rather selective against a panel of 38 kinases. Compound 18, a NOD1/NOD2 pathway inhibitor, along with compound 2, a selective NOD1 pathway inhibitor, displays acceptable ADMET properties and inhibition of key pro-inflammatory cytokines in a DSS-induced murine model of colitis. In this context, this study demonstrates the potential of NOD-RIPK2 inhibitors as a therapeutic solution for IBD.

中文翻译：

新型强效 RIPK2 抑制剂通过阻断 NOD 炎症通路作为结肠炎的有前途的治疗途径

炎症性肠病（IBD）是以肠道慢性炎症为特征的疾病。受体相互作用的丝氨酸/苏氨酸蛋白激酶 2 是核苷酸寡聚化结构域（NOD）样受体（NLR） 1 （NOD1）和 NOD2 炎症通路的关键介质，已被证明参与这些病理的发展。在这里，我们报道了一系列喹唑啉作为受体相互作用丝氨酸/苏氨酸蛋白激酶 2 （RIPK2）抑制剂的发展，其中大多数高度阻断 NOD1 通路，而其他喹唑啉则阻断两种 NOD 通路。我们最好的 9 种化合物显示出 RIPK2 的高细胞参与，并且对一组 38 种激酶具有相当的选择性。化合物 18 是一种 NOD1/NOD2 通路抑制剂，化合物 2 是一种选择性 NOD1 通路抑制剂，在 DSS 诱导的结肠炎小鼠模型中显示出可接受的 ADMET 特性和对关键促炎细胞因子的抑制作用。在此背景下，本研究证明了 NOD-RIPK2 抑制剂作为 IBD 治疗解决方案的潜力。

更新日期：2024-08-27

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