N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships, and in Vivo Efficacy.,Journal of Medicinal Chemistry

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N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships, and in Vivo Efficacy.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-05-28 , DOI: 10.1021/acs.jmedchem.9b00611
Hao Zhang ₁ , Lijuan Xu ₁ , Xia Qin ₂ , Xiaofei Chen ₃ , Hui Cong _{1,

3} , Longmiao Hu ₂ , Long Chen ₃ , Zhenyuan Miao ₃ , Wannian Zhang _{1,

3} , Zhenyu Cai _{2,

4} , Chunlin Zhuang _{1,

3,

5}

Affiliation

Necroptosis, a form of programmed cell death, plays a critical role in various diseases, including inflammatory, infectious, and degenerative diseases. We previously identified N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) (6) as a potent inhibitor of necroptosis by targeting both receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) kinases. Herein, we performed three rounds of structural optimizations of TAK-632 and elucidated structure-activity relationships to generate more potent inhibitors by targeting RIPK3. The analogues with carbamide groups exhibited great antinecroptotic activities, and compound 42 showed >60-fold selectivity for RIPK3 than RIPK1. It blocked necrosome formation by specifically inhibiting the phosphorylation of RIPK3 in necroptotic cells. In a tumor necrosis factor-induced systemic inflammatory response syndrome model, it significantly protected mice from hypothermia and death at a dose of 5 mg/kg, which was much more effective than TAK-632. Moreover, it showed favorable and druglike pharmacokinetic properties in rats with an oral bioavailability of 25.2%. Thus, these RIPK3-targeting small molecules represent promising lead structures for further development.

中文翻译：

N-（7-氰基-6-（4-氟-3-（2-（3-（三（三氟甲基）苯基）乙酰胺基）苯氧基）苯并[d]噻唑-2-基）环丙烷甲酰胺（TAK-632）类似物为新型通过靶向受体相互作用蛋白激酶3（RIPK3）的坏死病抑制剂：合成，结构活性关系和体内功效。

坏死病是程序性细胞死亡的一种形式，它在各种疾病（包括炎性，传染性和退行性疾病）中起关键作用。我们之前确定了N-（7-氰基-6-（4-氟-3-（2-（3-（三氟甲基）苯基）乙酰胺基）苯氧基）苯并[d]噻唑-2-基）环丙烷甲酰胺（TAK-632）（6）通过靶向与受体相互作用的蛋白激酶1（RIPK1）和3（RIPK3）激酶来作为坏死性强效抑制剂。在本文中，我们进行了三轮TAK-632的结构优化和阐明的结构活性关系，以针对RIPK3产生更有效的抑制剂。具有氨基甲酸酯基团的类似物表现出很大的抗肿瘤活性，并且化合物42对RIPK3的选择性是RIPK1的> 60倍。它通过特异性抑制肾病细胞RIPK3的磷酸化来阻断坏死体的形成。在肿瘤坏死因子诱导的全身炎症反应综合征模型中，它以5 mg / kg的剂量显着保护小鼠免受体温过低和死亡的伤害，这比TAK-632更为有效。此外，它在大鼠中表现出良好的和类似药物的药代动力学特性，口服生物利用度为25.2％。因此，这些靶向RIPK3的小分子代表了有前途的前导结构，可用于进一步开发。它在大鼠中显示出良好的药物样药动力学特性，口服生物利用度为25.2％。因此，这些靶向RIPK3的小分子代表了有前途的前导结构，可用于进一步开发。它在大鼠中显示出良好的药物样药动力学特性，口服生物利用度为25.2％。因此，这些靶向RIPK3的小分子代表了有前途的前导结构，可用于进一步开发。

更新日期：2019-05-16

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