Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2,ACS Medicinal Chemistry Letters

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Discovery of 1,5-Dihydro-4H-imidazol-4-one Derivatives as Potent, Selective Antagonists of CXC Chemokine Receptor 2
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-04-08 , DOI: 10.1021/acsmedchemlett.1c00113
Jinxin Che ₁ , Zhilong Wang ₂ , Zheyuan Shen ₁ , Weihao Zhuang ₁ , Huazhou Ying ₁ , Yongzhou Hu ₁ , Youhong Hu _{3,

4} , Xin Xie _{2,

4} , Xiaowu Dong _{1,

5,

6}

Affiliation

CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) have been demonstrated to have critical roles in cancer metastasis. Because they share high homology sequences, it is still unclear how to design selective CXCR1 or CXCR2 antagonists. Based on a pharmacophore model we built, compound 2 bearing a 1,5-dihydro-4H-imidazol-4-one scaffold was identified as a selective CXCR2 antagonist with a low CXCR1 antagonism preference. Further optimization and structure–activity relationship studies led to compound C5 that overcame the disadvantages of compound 2 and performed with higher selectivity. It showed excellent oral bioavailability and in vitro anticancer metastasis activity. Further dynamic simulation of the molecular protein complex showed that the amino acid residue K320 of CXCR2 contributed most to the selectivity of C5. This study provides important clues for the design of new CXCR2 selective antagonists, and C5 can be a molecular tool for investigating the difference in the biological function of CXCR1 and CXCR2.

中文翻译：

发现 1,5-二氢-4H-咪唑-4-酮衍生物作为 CXC 趋化因子受体 2 的有效选择性拮抗剂

CXC 趋化因子受体 1 (CXCR1) 和 2 (CXCR2) 已被证明在癌症转移中具有关键作用。由于它们具有高度同源性序列，目前尚不清楚如何设计选择性CXCR1或CXCR2拮抗剂。基于我们建立的药效团模型，带有 1,5-二氢-4 H-咪唑-4-酮支架的化合物2被鉴定为具有低 CXCR1 拮抗偏好的选择性 CXCR2 拮抗剂。经过进一步的优化和构效关系研究，化合物C5克服了化合物2的缺点，具有更高的选择性。它表现出优异的口服生物利用度和体外抗癌转移活性。分子蛋白复合物的进一步动态模拟表明，CXCR2的氨基酸残基K320对C5的选择性贡献最大。该研究为设计新型CXCR2选择性拮抗剂提供了重要线索， C5可以作为研究CXCR1和CXCR2生物学功能差异的分子工具。

更新日期：2021-05-13

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