European Journal of Medicinal Chemistry最新文献

{"title":"Innovative design and potential applications of covalent strategy in drug discovery","authors":"Tianyong Tang, Jiaxiang Luo, Dan Zhang, Yang Lu, Wen Liao, Jifa Zhang","doi":"10.1016/j.ejmech.2024.117202","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117202","url":null,"abstract":"Covalent inhibitors provide persistent inhibition while maintaining excellent selectivity and efficacy by creating stable covalent connections with specific amino acids in target proteins. This technique enables the precise inhibition of previously undruggable targets, lowering the frequency of administration and potentially bypassing drug resistance. Because of these advantages, covalent inhibitors have tremendous potential in treating cancer, inflammation, and infectious illnesses, making them extremely important in modern pharmacological research. Covalent inhibitors targeting EGFR, BTK, and KRAS (G12X), which overcome drug resistance and off-target, non-\"medicinal\" difficulties, as well as covalent inhibitors targeting SARS-CoV-2 M^pro, have paved the way for the development of new antiviral medicines. Furthermore, the use of covalent methods in drug discovery procedures, such as covalent PROTACs, covalent molecular gels, covalent probes, CoLDR, and Dual-targeted covalent inhibitors, preserves these tactics' inherent features while incorporating the advantages of covalent inhibitors. This synthesis opens up new therapeutic opportunities. This review comprehensively examines the use of covalent techniques in drug discovery, emphasizing their transformational potential for future drug development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"70 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886829","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}

{"title":"Identification of a Selective Pyruvate Dehydrogenase Kinase 1 (PDHK1) Chemical Probe by Virtual Screening","authors":"Mason A. Baber, Mya D. Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L. Toogood","doi":"10.1016/j.ejmech.2024.117210","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117210","url":null,"abstract":"PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth <em>in vitro</em> and <em>in vivo</em>, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound <strong>7</strong> as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound <strong>10</strong>. Structure-activity studies based on <strong>10</strong> identified <strong>17</strong> as a low μM inhibitor of PDHK1 (IC₅₀ = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound <strong>17</strong> inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify <strong>17</strong> as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886827","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}

{"title":"A review of kappa opioid receptor antagonists and their clinical trial landscape","authors":"Maloba M.M. Lobe, Saroj Verma, Vaishali M. Patil, Malliga R. Iyer","doi":"10.1016/j.ejmech.2024.117205","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117205","url":null,"abstract":"Myriad signaling pathways are implicated in neuropsychiatric disorders, yet many mechanisms are unknown and current treatment options are limited. The intriguing dynorphin/kappa opioid receptor (KOR) system that is widely distributed throughout the brain appears to be essential in regulating many physiological and pathophysiological processes. This review explores up to date advances on the relationship between the dynorphin/KOR system with a particular focus on the KOR antagonist compounds tested as clinical candidates that could offer potential treatment options for CNS disorders.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884496","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}

{"title":"Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice","authors":"Guiyan Huang, Yu Lin, Jianping Zhao, Junlei Zhang, Yuexin Du, Mingyue Xiao, Heng Li, Zhong Chen, Naixin Kang, Ikhlas A. Khan, Yanli Liu, Bin Huang, Qiongming Xu","doi":"10.1016/j.ejmech.2024.117184","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117184","url":null,"abstract":"Corosolic acid (CA), a natural triterpenoid, exhibits various biological activities and is often called a plant-derived insulin due to its significant hypoglycemic effects, making it especially beneficial for individuals with diabetes or high blood glucose levels. However, CA has notable in vitro toxicity, low water solubility, and poor pharmacokinetic properties. To address these limitations, a series of CA derivatives were synthesized, resulting in the identification of derivative H26, which demonstrates a significantly enhanced hypoglycemic effect, reduced toxicity, and improved pharmacokinetic characteristics compared to CA. To identify the target protein of CA and investigate its therapeutic potential, a chemical probe derived from natural products, called CA-biotin, was designed and synthesized. By employing an avidin-biotin affinity binding system, we distinguished the differential protein bands between CA-biotin and biotin. This quantitative proteomic analysis revealed, for the first time, that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) directly binds to CA. The interaction between H26 and MCCC1 was examined in vitro. The research on the mechanisms by which CA and H26 address Type 2 diabetes mellitus (T2DM) concentrated on the insulin resistance signaling pathway, specifically targeting MCCC1. The results indicated that H26 shows significant promise as a potential hypoglycemic agent, while MCCC1 may serve as a valuable target for addressing insulin resistance. This presents a promising opportunity for developing new medications aimed at improving the health of patients with type 2 diabetes mellitus (T2DM) or hyperglycemia.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"123 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884494","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}

{"title":"Design, Synthesis and Biological Evaluation of Galantamine Analogues for Cognitive Improvement in Alzheimer's Disease","authors":"Mengzhen Li, Chao Ma, Yao Li, Hanxun Wang, Xiaomeng Xiu, Xueqi Zhao, Peng Liu, Huali Yang, Maosheng Cheng","doi":"10.1016/j.ejmech.2024.117198","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117198","url":null,"abstract":"Galantamine plays a crucial role in the management of brain disorders. In this study, a series of galantamine analogues were designed, synthesized and evaluated as potential therapeutic agents for Alzheimer's disease (AD). Compound <strong>C2</strong>, a dual inhibitor of cholinesterase, was obtained by introducing a benzylpyridine ring to the hydroxyl group of galantamine. Compared to galantamine (<em>h</em>AChE, IC₅₀ = 1529 ± 6 nM), <strong>C2</strong> exhibited excellent inhibitory activities against <em>h</em>AChE (IC₅₀ = 513.90 ± 9.60 nM) and <em>h</em>BuChE (IC₅₀ = 357.77 ± 10.24 nM). Further studies revealed that <strong>C2</strong> possessed significant abilities to protect PC12 cells from H₂O₂-induced apoptosis and reactive oxygen species (ROS) production. The acute toxicity test <em>in vivo</em> indicated that <strong>C2</strong> exhibited a remarkable safety profile. Whether in the acute memory impairment induced by the Aβ_1-42 model or in the amnesia induced by the scopolamine model, oral administration of <strong>C2</strong> demonstrated superior improvement on cognition and spatial memory. In summary, both <em>in vitro</em> and <em>in vivo</em> results suggest that <strong>C2</strong> deserves to be further explored as an anti-AD agent.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884498","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}

{"title":"Recent Progress in the Development of Peptide-Drug Conjugates (PDCs) for Cancer Therapy","authors":"Haiqi He, Xin Deng, Zhijie Wang, Jianjun Chen","doi":"10.1016/j.ejmech.2024.117204","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117204","url":null,"abstract":"Peptide-drug conjugates (PDCs) are emerging therapeutic agents composed of peptides, linkers, and payloads, which possess favorable targeting capability and can deliver enough payloads to the tumor sites with minimized impact on healthy tissues. However, only a few PDCs have been approved for clinical use so far. To advance the research on PDCs, this review summarizes the approved PDCs, and PDCs in clinical and preclinical stages based on the payload types. Additionally, the biological activity and pharmacokinetic properties of preclinical PDCs are detailedly described. Lastly, the challenges and future development directions of PDCs are discussed. This review aims to inspire insights into the development of PDCs for cancer treatment.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884499","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}

{"title":"Corrigendum to “Discovery of indazole inhibitors for heat shock protein 90 as anti-cancer agents” [Eur. J. Med. Chem. (2024) 116620]","authors":"Minh Thanh La, Van-Hai Hoang, Raghaba Sahu, Cong-Truong Nguyen, Gibeom Nam, Hyun-Ju Park, Minsu Park, Yoon-Jae Kim, Ji Young Kim, Jihyae Ann, Jae Hong Seo, Jeewoo Lee","doi":"10.1016/j.ejmech.2024.117194","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117194","url":null,"abstract":"The authors regret the omission of funding information for grant number 2023R1A2C3004010 in the Acknowledgments section of the original publication. The authors would like to amend the Acknowledgments as follows:","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879903","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}

{"title":"Discovery of Novel Bicyclic and Tricyclic Cyclohepta[b]thiophene Derivatives as Multipotent AChE and BChE Inhibitors, In-Vivo and In-Vitro Assays, ADMET and Molecular Docking Simulation","authors":"Eman A. Fayed, Samiha Ahmed El-Sebaey, Maha A. Ebrahim, Karema Abu-Elfotuh, Reda El-Sayed Mansour, Ehsan Khedre Mohamed, Ahmed M.E. Hamdan, Faleh Turki Al-subaie, Gharam Saad Albalawi, Tariq Mohammed Albalawi, Amira M. Hamdan, Asmaa A. Mohammed, Triveena M. Ramsis","doi":"10.1016/j.ejmech.2024.117201","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117201","url":null,"abstract":"Alzheimer’s disease (AD) is primarily caused by oxidative stress, hyperphosphorylated τ-protein aggregation, and amyloid-<em>β</em> deposition. Changes in dopaminergic and serotoninergic neurotransmitter pathways are linked to certain symptoms of AD. Derivatives of bicyclic and tricyclic cyclohepta[<em>b</em>]thiophene were developed to identify new potential candidates as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors for the treatment of AD. All synthesized compounds exhibited AChE inhibition with IC₅₀ values below 15 μM, while all compounds exhibited BChE inhibition with IC₅₀ values below 25 μM. Compounds <strong>9</strong> and <strong>12</strong> exhibited AChE inhibitory activities with IC₅₀ values of 0.51 μM and 0.55 μM, respectively. Compounds <strong>5</strong> and <strong>9</strong> demonstrated excellent inhibitory activity against BChE with IC₅₀ values of 2.9 μM and 2.48 μM, respectively. Compounds <strong>9</strong>, <strong>13</strong>, and <strong>14</strong> were found to be the most active in terms of the decrease in the escape latency time, with values comparable to that of Donepezil. Compounds <strong>10</strong>, <strong>11</strong>, and <strong>12</strong> exhibited promising effects on learning and memory. Compounds <strong>5</strong>, <strong>10</strong>, <strong>11</strong>, and <strong>12</strong> exhibited promising SAP values of 70.67%, 71.5%, 74.33% and 73.83%, respectively. Other biomarkers were evaluated in rat brains including TAC, MDA, SOD, BDNF, IL-<em>β</em> and TNF-<em>α</em>. Fundamental features of ADMET have been computed <em>in-silico</em> for synthesized compounds. Molecular docking was performed to confirm the binding of the novel compounds to the targets.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884495","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}

{"title":"Glycoconjugates of Adefovir and Tenofovir as Asialoglycoprotein-Mediated Anti-HBV Prodrugs with Enhanced Liver Targeting","authors":"Lei Chen, Mingzhenlong Deng, Wanli Yan, Ziwei Zeng, Di Chen, Yonglong Zhao, Yisong Wu, Yan Li, Bin He","doi":"10.1016/j.ejmech.2024.117207","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117207","url":null,"abstract":"Hepatitis B virus (HBV) infection remains a significant global health challenge, often leading to severe liver complications such as cirrhosis and cancer. Current treatments rely heavily on nucleos(t)ide analogs like adefovir and tenofovir due to their potent antiviral effects. However, their clinical utility is limited by insufficient liver targeting, leading to off-target side effects, particularly nephrotoxicity. To improve liver-specific drug delivery and reduce adverse effects, we designed novel liver-targeted prodrugs by conjugating adefovir and tenofovir with N-acetylgalactosamine (GalNAc) and tris-GalNAc ligands, which have high affinity for the asialoglycoprotein receptor (ASGPR) predominantly expressed in hepatocytes. Four prodrugs (<strong>A1, A2, T1, and T2</strong>) were synthesized and evaluated for cytotoxicity, maximum tolerated dose, anti-HBV activity, metabolic stability, pharmacokinetics, and liver-targeting properties. The prodrugs exhibited low cytotoxicity, robust anti-HBV activity, and enhanced selectivity compared to their parent drugs. Notably, the tris-GalNAc conjugates <strong>A2</strong> and <strong>T2</strong> demonstrated superior liver targeting, showing a threefold higher concentration in the liver compared to the kidneys, thus minimizing renal exposure. These findings suggest that GalNAc and tris-GalNAc conjugation is a promising strategy for enhancing the therapeutic efficacy and safety of adefovir and tenofovir, with potential for further optimization as liver-targeted anti-HBV prodrugs.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884497","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}

{"title":"Design, Synthesis, and Biological Evaluation of Ponatinib-based N-Phenylpyrimidine-2-amine Derivatives as Novel Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors","authors":"Lei Han, Yu Yu, Ping Deng, Shuai Wang, Junchi Hu, Shuang Wang, Jiecheng Zheng, Junhao Jiang, Yongjun Dang, Rui Long, Zongjie Gan","doi":"10.1016/j.ejmech.2024.117206","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117206","url":null,"abstract":"Fibroblast growth factor receptor 4 (FGFR4) has been proven to be a promising target for FGFR-driven HCC therapy. Great efforts have been devoted to the discovery of FGFR4 inhibitors. In this article, a new class of Ponatinib-based <em>N</em>-phenylpyridine-2-amine derivatives was designed and synthesized as covalent and irreversible FGFR4 selective inhibitors through a rational drug design strategy. The representative compound <strong>10f</strong> displayed significant FGFR4 inhibition and reasonable selectivity. Meanwhile, compound <strong>10f</strong> strongly suppressed the proliferation of FGFR4 dependent HCC cells both <em>in vitro</em> and <em>in vivo</em> by inhibiting the FGFR4 signaling pathway. Moreover, the irreversible binding to Cys552 in FGFR4 of compound <strong>10f</strong> was also characterized by LC-MS/MS. These results provide evidence of <strong>10f</strong> as a potential lead compound targeting FGFR4 for anti-HCC agent development.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884500","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}