利用双模式 RIPK1 配体开发跨物种抗颈突变抑制化合物。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-19 DOI:10.1016/j.bmcl.2024.129970

József Levente Petró , Péter Bana , Nikolett Linke , Judit Eszter Szabó , Krisztina Katalin Szalai , Ildikó Kálomista , Csaba Gábor Vass , Gábor Hornyánszky , István Greiner , János Éles

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引用次数: 0

摘要

与受体相互作用的丝氨酸/苏氨酸蛋白激酶1（RIPK1）在细胞死亡和炎症中起着至关重要的作用。开发新型 RIPK1 介导的坏死抑制剂的一个可行方法是将已知 RIPK1 抑制剂的不同结合模式混合到一个分子中。在此，我们报告了新型混合型抑制剂的合成和生物学评价。以 Eclitasertib 为起点，运用我们以前发表的有关环丙二酸的知识，我们成功地鉴定出了一个活性化合物库。我们在小鼠体内进行了药代动力学和体内低体温研究，并对最平衡、最有前景的化合物的活性对映体进行了评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

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Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.