European Journal of Medicinal Chemistry最新文献

Corrigendum to "Development of a potent BET inhibitor for the treatment of renal fibrosis" [Eur. J. Med. Chem., 295 (2025), 117822]. “开发一种治疗肾纤维化的有效BET抑制剂”的勘误表[欧洲]。医学化学。生态学报，295 (2025),117822 [j]。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-11-15 Epub Date: 2026-08-20 DOI: 10.1016/j.ejmech.2026.119243

Jianhang Huang, Na Zhao, Jian Li, Jiayi Zhu, Guoao Liang, Xing Chen, Naiyuan Wang, Huilong Zhu, Ningning Pang, Chunmei An, Xiaochun Xiong

引用次数: 0

Design and Optimization of 5-Hydroxy-4H-benzo[1,4]oxazin-3-one-Derived β2-Adrenoceptor Agonists with Potent Anti-Asthmatic Activity 具有抗哮喘活性的5-羟基- 4h -苯并[1,4]恶嗪-3- 1衍生物β2-肾上腺素能受体激动剂的设计与优化

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-02 DOI: 10.1016/j.ejmech.2026.119297

Lanyan Ma, Zhengxing Zhi, Zhenli Li, Li Pan, Yin Sun, Yang Liu, Maosheng Cheng, Gang Xing

{"title":"Design and Optimization of 5-Hydroxy-4H-benzo[1,4]oxazin-3-one-Derived β2-Adrenoceptor Agonists with Potent Anti-Asthmatic Activity","authors":"Lanyan Ma, Zhengxing Zhi, Zhenli Li, Li Pan, Yin Sun, Yang Liu, Maosheng Cheng, Gang Xing","doi":"10.1016/j.ejmech.2026.119297","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119297","url":null,"abstract":"β<ce:inf loc=\"post\">2</ce:inf>-Adrenergic receptor (β<ce:inf loc=\"post\">2</ce:inf>-AR) agonists, as classic bronchodilators, serve as the cornerstone for asthma treatment. Herein, we designed and synthesized a series of derivatives based on the 5-hydroxy-4<ce:italic>H</ce:italic>-benzo[1,4]oxazin-3-one scaffold. Based on a comprehensive evaluation of four core indicators, including cAMP accumulation assays in HEK293 cells overexpressing human β<ce:inf loc=\"post\">2</ce:inf>-AR or β<ce:inf loc=\"post\">1</ce:inf>-AR, guinea pig tracheal strip assays, and in <ce:italic>vitro</ce:italic> cytotoxicity, compound <ce:bold>C3</ce:bold> exhibited the best overall performance (β<ce:inf loc=\"post\">2</ce:inf>-AR EC<ce:inf loc=\"post\">50</ce:inf> = 7 pM, β<ce:inf loc=\"post\">2</ce:inf>/β<ce:inf loc=\"post\">1</ce:inf> selectivity > 97-fold; isolated tracheal relaxation E<ce:inf loc=\"post\">max</ce:inf> = 136.88, pD<ce:inf loc=\"post\">2</ce:inf> = 8.32; human bronchial epithelial cell BEAS-2B CC<ce:inf loc=\"post\">50</ce:inf> = 50.07 μM) and was selected as the candidate molecule. In a mouse asthma model, <ce:bold>C3</ce:bold> administered at 200 μg/kg/day (458.5 nmol/kg/day) markedly suppressed inflammatory cell activity and improved lung function, showing anti-asthmatic efficacy comparable to that of salmeterol at 300 μg/kg/day (721.7 nmol/kg/day). In conclusion, <ce:bold>C3</ce:bold> is a β<ce:inf loc=\"post\">2</ce:inf>-AR agonist with potential application value, holding promise for the treatment of asthma.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MLI-DTA: An Interpretable Multimodal Framework with Multi-Level Interactions for Drug-Target Affinity Prediction MLI-DTA：一个可解释的多模态框架，具有多层次的相互作用，用于药物-靶点亲和力预测

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-02 DOI: 10.1016/j.ejmech.2026.119301

Yuning Liu, Guangze Wang, Dan Liu, Jun Wang, Xiaohu Shi, Shiqian Han

{"title":"MLI-DTA: An Interpretable Multimodal Framework with Multi-Level Interactions for Drug-Target Affinity Prediction","authors":"Yuning Liu, Guangze Wang, Dan Liu, Jun Wang, Xiaohu Shi, Shiqian Han","doi":"10.1016/j.ejmech.2026.119301","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119301","url":null,"abstract":"Drug-target affinity prediction provides a computational basis for virtual screening and drug repositioning optimization by estimating the binding strength between compounds and target proteins. Existing deep learning methods have evolved from early SMILES/amino acid sequence modeling to graph neural networks and multi-modal fusion. However, there are still three challenges: one-dimensional sequence models struggle to explicitly represent atomic connections and residue interactions; some graph models incorporate molecular or protein contact graphs, but often fail to properly align the semantics of drugs with those of proteins; some multi-modal approaches simply stack multiple source features together, without organizing the interaction processes based on different levels of binding information. To address these issues, this paper proposes MLI-DTA, a hierarchical multi-source feature fusion network based on multi-level attention. MLI-DTA encodes both sequence and graph modalities of drugs and targets. At a finer granularity level, the Bilinear Attention Network models high-level pairings between drug fragments and protein sequence fragments. At a medium granularity level, the Global Graph Cross-Attention mechanism aligns the topological structure of drugs with the contact graph of proteins. Additionally, the Multi-head Collaborative Attention mechanism integrates graph interaction vectors with sequence-level global representations. At a coarser granularity level, the Gate Fusion mechanism dynamically combines global features from both sequences and graphs. Multiple layers of information are combined to create an affinity predictor, enabling the model to utilize both sequence interactions, graph topological semantics, and global context simultaneously. Experiments conducted in the Davis and KIBA benchmarks demonstrate that MLI-DTA performs exceptionally well.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a highly selective FLT3-ITD inhibitor with potent antileukemic activity based on 4-(2-fluorophenoxy)pyridine scaffold. 基于4-（2-氟苯氧基）吡啶支架的具有有效抗白血病活性的高选择性FLT3-ITD抑制剂的发现

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119289

Zhongyuan Wang, Yiwei Zhang, Lin Li, Yunfeng Wang, Dan Yang, Qingmei Song, Qingqing Fu, Dongsheng Zhao, Lei Tang, Weiwei Ouyang, Yue'e Chai, Weike Liao

{"title":"Discovery of a highly selective FLT3-ITD inhibitor with potent antileukemic activity based on 4-(2-fluorophenoxy)pyridine scaffold.","authors":"Zhongyuan Wang, Yiwei Zhang, Lin Li, Yunfeng Wang, Dan Yang, Qingmei Song, Qingqing Fu, Dongsheng Zhao, Lei Tang, Weiwei Ouyang, Yue'e Chai, Weike Liao","doi":"10.1016/j.ejmech.2026.119289","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.119289","url":null,"abstract":"Acute myeloid leukemia (AML) driven by FLT3-ITD mutations remains a therapeutic challenge with limited treatment options. Herein, we report the design, synthesis, and biological evaluation of a series of 4-(2-fluorophenoxy)pyridine derivatives featuring an imidazolidinone carboxamide linker as potent FLT3-ITD inhibitors. Systematic structure-activity relationship exploration identified compound 18p as the optimal candidate, which displayed exceptional enzymatic potency against FLT3-ITD (IC50 = 1.1 nM) and single-digit nanomolar antiproliferative activity against FLT3-ITD driven AML cell lines (BaF3-FLT3-ITD IC50 = 5.7 nM; MOLM-13 IC50 = 1.6 nM). Compound 18p demonstrated a marked selectivity profile, discriminating FLT3-ITD from FLT3-WT and sparing normal PBMCs and a broad panel of solid tumor cells. Kinome profiling revealed that 18p maintained high selectivity over c-Kit, CDKs, FGFRs, and the majority of 60 tested kinases, with PDGFRβ identified as the principal off-target liability. Mechanistically, 18p suppressed FLT3 autophosphorylation and downstream STAT5, AKT, and ERK signaling more effectively than gilteritinib at equimolar concentrations, and induced potent G1-phase arrest and apoptosis in MOLM-13 cells. In the MV4-11 xenograft model, oral administration of 18p at 10 mg/kg achieved 80% tumor growth inhibition, comparable to gilteritinib at 2.5 mg/kg, with concomitant suppression of Ki67 and p-STAT5 and induction of cleaved caspase-3 and γH2AX in tumor tissues. Histopathological examination of major organs confirmed an absence of overt toxicity. These findings position 18p as a promising FLT3-ITD inhibitor and provide valuable insights for further development of mutation-selective AML therapeutics.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"319 ","pages":"119289"},"PeriodicalIF":6.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and Synthesis of Novel Peptide-Based Degraders against Wild Type and Gatekeeper Mutants FGFR1 for the Treatment of NSCLC 针对野生型和守门人突变FGFR1的新型肽基降解剂的设计和合成用于治疗非小细胞肺癌

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119296

Ziyu Tian,Luwei Fu,Xuanxuan Yan,Yizhu Chen,Wenju Yang,Yingqun Chen,Haiyan Liu,Yuepao Cai,Shijie Dai

引用次数: 0

FDA-approved imidazole- and benzimidazole-based drugs: An update. fda批准的咪唑和苯并咪唑类药物：最新进展。

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119281

Jingjing Du, Qianxue Wei, Xinming Chen, Xiuyang Chen, Tiantian Zhang, Danye Zhang, Xian Li, Ye Yang, Yang Wang

引用次数: 0

A hierarchical targeting one-for-all small-molecule enabling multimodal tumor therapy via energy blockade and heat-tolerance suppression 通过能量阻断和耐热性抑制，分层靶向“一刀切”小分子实现多模式肿瘤治疗

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119299

Zhizhe Li,Haonan Zheng,Yingying Ma,Tingting Li,Shuang Ma,Mi Li,Haiyan Xu,Shide Zheng,Hongqing Guo,Xinyu Wang,Weige Zhang,Qi Guan

引用次数: 0

Structure-Guided Discovery of HIV-1 Capsid Inhibitors: From Diverse Binding Sites to Resistance-Resilient Antiviral Strategies 结构引导下HIV-1衣壳抑制剂的发现：从不同的结合位点到耐药弹性抗病毒策略

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119307

Yuyan Li,Mei Wang,Lin Sun,Shujing Xu,Peng Zhan

引用次数: 0

Discovery of Novel 7,8-Dihydro-1H-purine Derivatives as Potent Dual DNA-PK/HDAC Inhibitors against Solid Tumors 新型7,8-二氢- 1h -嘌呤衍生物作为实体肿瘤有效的双DNA-PK/HDAC抑制剂的发现

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119298

Zhihao Hu,Shuqing Li,Jinjin Lai,Binbin Cheng,Wanyi Pan,Chengpeng Tao,Xiaopeng Peng

引用次数: 0

A Combination of MD Derived Pharmacophores and Structure-Based Strategy Identifies Dual Allosteric Inhibitors of NS2B-NS3 Proteases in Zika and West Nile Viruses MD衍生药效团和基于结构的策略联合鉴定寨卡病毒和西尼罗河病毒NS2B-NS3蛋白酶的双变构抑制剂

IF 6.7 2区医学

European Journal of Medicinal Chemistry Pub Date : 2026-09-01 DOI: 10.1016/j.ejmech.2026.119306

Antonio Lupia,Salvatore Nieddu,Laura Demuru,Erica Sanna,Alessia Onali,Roberta Emmolo,Paolo Malune,Simona Distinto,Giulia Atzeni,Annalaura Paulis,Rita Meleddu,Filippo Cottiglia,Francesca Esposito,Angela Corona,Sharon D. Bryant,Elias Maccioni,Enzo Tramontano

引用次数: 0