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

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
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引用次数: 0

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.
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来源期刊
Journal of Medicinal Chemistry
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.
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