Discovery of Safe COX-2 Inhibitors: Achieving Reduced Colitis Side Effects through Balanced COX Inhibition.

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-02-27 DOI:10.1002/cmdc.202500096
Xinlin Zhu, Qin Li, Junhui Wu, Zhiran Ju
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引用次数: 0

Abstract

The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21 d (IC50 value=1.35 μM, selectivity profile (IC50 (COX-1)/IC50 (COX-2)=22.34)). In vivo assays demonstrated that 21 d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.

安全COX-2抑制剂的发现:通过平衡COX抑制减少结肠炎副作用。
环氧化酶-2 (COX-2)抑制不平衡相关的严重不良反应继续对当代抗炎药物的开发构成重大挑战。近年来,COX-2抑制剂药物开发的方法已经从关注COX-2的高选择性抑制转向强调更适度选择性的策略。诱导型COX-2和组成型环氧化酶-1 (COX-1)亚型之间的氨基酸序列和结构相似性为设计下一代平衡型COX-2抑制剂提供了巨大的机遇和挑战。作为我们正在进行的发现新型和更安全的COX-2抑制剂的研究的一部分,我们在这里报告了一种高效和平衡的COX-2抑制剂21d (IC50值= 1.35µM,选择性谱(IC50 (COX-1)/IC50 (COX-2) = 22.34))。体内实验表明,21d显著减轻了组织损伤,并对葡聚糖硫酸钠(DSS)诱导的急性结肠炎提供了强有力的保护。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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