Identification of 5-(2,3-Dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model,Journal of Medicinal Chemistry

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Identification of 5-(2,3-Dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-11-27 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01652
Yueshan Li ₁ , Yu Xiong ₁ , Guo Zhang , Liting Zhang ₁ , Wei Yang , Jiao Yang ₁ , Luyi Huang ₁ , Zeen Qiao ₁ , Zhuang Miao ₁ , Guifeng Lin ₁ , Qiu Sun ₁ , Ting Niu , Lijuan Chen ₁ , Dawen Niu ₁ , Linli Li , Shengyong Yang ₁

Affiliation

We herein report the structural optimization and structure–activity relationship studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity (K_D) of 0.004 μM and an enzymatic IC₅₀ value of 0.011 μM and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, compound 22b exhibited excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.

中文翻译：

5-（2,3-二氢-1 H-吲哚-5-基）-7 H-吡咯并[2,3- d ]嘧啶-4-胺衍生物作为新型的受体相互作用蛋白激酶1（ RIPK1）抑制剂，在肿瘤转移模型中显示有效活性

我们在这里报告了5-（2,3-dihydro-1 H-吲哚-5-基）-7 H-吡咯并[2,3- d ]嘧啶-4-胺衍生物的结构优化和构效关系研究。新型的受体相互作用蛋白激酶1（RIPK1）抑制剂。在所有获得的RIPK1抑制剂中，1-（5- {4-氨基-7-乙基-7 H-吡咯并[2,3- d ]嘧啶-5-基} -2,3-二氢-1 H-吲哚-1 -基）-2- [3-（三氟甲氧基）苯基]乙-1-酮（22b）是最活跃的。该化合物以0.004μM的结合亲和力（K _D）和酶促IC ₅₀有效抑制RIPK1值为0.011μM，并且还显示出良好的激酶选择性。它可以有效地保护细胞免于坏死性坏死，并减轻肿瘤细胞在体外和体内诱导的血管内皮细胞的坏死细胞死亡。重要的是，化合物22b在实验性B16黑色素瘤肺转移模型中显示出优异的抗转移活性。它还显示出良好的药代动力学性质。总体而言，22b可能是预防肿瘤转移的有前途的药物。

更新日期：2018-11-27

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