发现一种新的p38α-MK2复合物抑制剂作为自身免疫性疾病的潜在选择

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-01-09 DOI:10.1021/acs.jmedchem.4c01925

Donglin Fu, Zimo Yang, Xiangyu Jia, Tian Han, Long Han, Xiaobing Zhang, Yuanfeng Xia, Siqin Wang, Lei Jin, Zhilong Hu, Fanglong Yang

{"title":"发现一种新的p38α-MK2复合物抑制剂作为自身免疫性疾病的潜在选择","authors":"Donglin Fu, Zimo Yang, Xiangyu Jia, Tian Han, Long Han, Xiaobing Zhang, Yuanfeng Xia, Siqin Wang, Lei Jin, Zhilong Hu, Fanglong Yang","doi":"10.1021/acs.jmedchem.4c01925","DOIUrl":null,"url":null,"abstract":"The p38α-MK2 signaling axis plays an important role in the inflammatory response of cells. Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38α-MK2 complex and improve pharmacokinetic properties. First, the magic F strategy was utilized to obtain compound 21, which displayed a 60-fold increase in tumor necrosis factor α inhibition and a 600-fold increase in interleukin-6 inhibition. Molecular dynamics simulations revealed insights into the binding mode of fluorinated molecules. Subsequently, introducing a methyl group and a fluorine group led to compound 36, which showed improved pharmacokinetic properties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced arthritis model showed that compound 36 had a robust inflammation inhibitory effect and joint repair ability. Currently, compound 36 is being considered for preclinical development as a potential treatment for inflammatory diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"204 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of a Novel p38α-MK2 Complex Inhibitor as a Potential Choice for Autoimmune Diseases\",\"authors\":\"Donglin Fu, Zimo Yang, Xiangyu Jia, Tian Han, Long Han, Xiaobing Zhang, Yuanfeng Xia, Siqin Wang, Lei Jin, Zhilong Hu, Fanglong Yang\",\"doi\":\"10.1021/acs.jmedchem.4c01925\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The p38α-MK2 signaling axis plays an important role in the inflammatory response of cells. Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38α-MK2 complex and improve pharmacokinetic properties. First, the magic F strategy was utilized to obtain compound 21, which displayed a 60-fold increase in tumor necrosis factor α inhibition and a 600-fold increase in interleukin-6 inhibition. Molecular dynamics simulations revealed insights into the binding mode of fluorinated molecules. Subsequently, introducing a methyl group and a fluorine group led to compound 36, which showed improved pharmacokinetic properties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced arthritis model showed that compound 36 had a robust inflammation inhibitory effect and joint repair ability. Currently, compound 36 is being considered for preclinical development as a potential treatment for inflammatory diseases.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"204 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-01-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c01925\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01925","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

p38α-MK2信号轴在细胞炎症反应中起重要作用。我们对CDD-450进行了一系列优化，旨在增强其对p38α-MK2复合物的抑制作用，改善其药动学性质。首先，利用神奇的F策略获得化合物21，其对肿瘤坏死因子α的抑制作用增加了60倍，对白细胞介素6的抑制作用增加了600倍。分子动力学模拟揭示了氟化分子的结合模式。随后，引入甲基和氟基团得到化合物36，该化合物在大鼠和狗体内表现出改善的药代动力学特性。Lewis大鼠佐剂诱导的关节炎模型评价表明，化合物36具有较强的炎症抑制作用和关节修复能力。目前，化合物36正被考虑用于临床前开发，作为炎症性疾病的潜在治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Discovery of a Novel p38α-MK2 Complex Inhibitor as a Potential Choice for Autoimmune Diseases

The p38α-MK2 signaling axis plays an important role in the inflammatory response of cells. Here, we carried out a series of optimizations on CDD-450, aiming to enhance inhibition of the p38α-MK2 complex and improve pharmacokinetic properties. First, the magic F strategy was utilized to obtain compound 21, which displayed a 60-fold increase in tumor necrosis factor α inhibition and a 600-fold increase in interleukin-6 inhibition. Molecular dynamics simulations revealed insights into the binding mode of fluorinated molecules. Subsequently, introducing a methyl group and a fluorine group led to compound 36, which showed improved pharmacokinetic properties in rats and dogs. Evaluation in the Lewis rat adjuvant-induced arthritis model showed that compound 36 had a robust inflammation inhibitory effect and joint repair ability. Currently, compound 36 is being considered for preclinical development as a potential treatment for inflammatory diseases.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.