European Journal of Medicinal Chemistry最新文献_第4页

The prospects and challenges of small molecule drugs in the treatment of Duchenne muscular dystrophy 小分子药物治疗杜氏肌营养不良的前景与挑战

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-17 DOI: 10.1016/j.ejmech.2025.117980

Yi-Ming Peng , Yi-Ru Bai , Rui-Fang Li , Yi-Xin Xu , Hong-Min Liu , Shuo Yuan , Zhi-Peng Jin

引用次数: 0

Metabotropic glutamate receptor 5 in depression: Mechanisms and therapeutic potential 代谢性谷氨酸受体5在抑郁症中的作用：机制和治疗潜力

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-17 DOI: 10.1016/j.ejmech.2025.117976

Cunbao He , Junjie Zhang , Jingji Wang , Guoqi Zhu , Shaojie Yang

{"title":"Metabotropic glutamate receptor 5 in depression: Mechanisms and therapeutic potential","authors":"Cunbao He , Junjie Zhang , Jingji Wang , Guoqi Zhu , Shaojie Yang","doi":"10.1016/j.ejmech.2025.117976","DOIUrl":"10.1016/j.ejmech.2025.117976","url":null,"abstract":"<div><div>Glutamate serves as the primary excitatory neurotransmitter within the central nervous system (CNS), and disturbances in the glutamatergic system have been linked to a variety of CNS disorders, especially depression. In recent years, metabotropic glutamate receptor 5 (mGluR5) has attracted considerable attention for its crucial role in regulating glutamatergic transmission. In this review, we conducted a search of PubMed, Web of Science and Science Direct databases to explore the relationship between mGluR5 and depression, and summarized the antidepressant effects and mechanisms of action of various mGluR5 negative allosteric modulators (NAMs) based on the literatures in the past five years. A total of 112 articles meeting the screening criteria were included this review. We found that the pathological process of depression was accompanied by abnormally elevated levels of mGluR5 expression, and its hyperactivation might be involved in disease progression by impairing neuroplasticity. In addition, mGluR5 had the potential to interact with classical depressive targets. Accordingly, mGluR5 NAMs exerted antidepressant effects by directly or indirectly modulating synaptic plasticity, suppressing inflammatory responses, and regulating molecular pathways. Based on literature reports of mGluR5 NAMs, we conducted selective molecular docking simulations to validate their strong binding. Finally, we summarized the efficacy and safety data of mGluR5 modulators that had entered clinical trials. In conclusion, targeting the mGluR5 is a promising strategy to address the clinical need for more effective treatments for patients with depression, but the safety still needs attention.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117976"},"PeriodicalIF":6.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645678","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

Development of radiolabeling 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as potential molecular probes for excitatory amino acid transporter 2 放射性标记2-氧-2-（4-苯基哌嗪-1-酰基）乙酰胺衍生物作为兴奋性氨基酸转运蛋白潜在分子探针的研究进展

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-16 DOI: 10.1016/j.ejmech.2025.117981

Pengfei Song , Kehao Gong , Liyuan Xing , Jinping Kong , Donglang Jiang , Ze Wang , Qi Huang , Yihui Guan , Fang Xie , Junbin Han , Yingfang He

{"title":"Development of radiolabeling 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as potential molecular probes for excitatory amino acid transporter 2","authors":"Pengfei Song , Kehao Gong , Liyuan Xing , Jinping Kong , Donglang Jiang , Ze Wang , Qi Huang , Yihui Guan , Fang Xie , Junbin Han , Yingfang He","doi":"10.1016/j.ejmech.2025.117981","DOIUrl":"10.1016/j.ejmech.2025.117981","url":null,"abstract":"<div><div>Excitatory amino acid transporter 2 (EAAT2) is an appealing target for drug development, as it plays a crucial role in synaptic glutamate transport under physiological conditions and its malfunction is implicated in neurodegenerations. In this study, we designed and synthesized a series of 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as novel EAAT2 positive allosteric modulators (PAMs). [<sup>131</sup>I]<strong>2</strong> ([<sup>131</sup>I]SF-1) was successfully developed as a valuable tool for <em>in vitro</em> competitive binding assay. Structure-affinity relationship led to the identification of compound <strong>4</strong> with an inhibitory constant of 29 nM. In <em>ex vivo</em> biodistribution studies, [<sup>18</sup>F]<strong>4</strong> ([<sup>18</sup>F]SF-2) exhibited excellent brain penetration and sufficient reversibility in the rodent brains. Pretreatment with cold reference or previously reported EAAT2 PAMs resulted in significant reductions of radioactivity accumulations in the brain and spinal cord, confirming its high specificity <em>in vivo</em>. These findings present a valuable molecular probe to directly measure the interactions of the novel structures with EAAT2 and open an opportunity to non-invasively monitor EAAT2 expression through PET neuroimaging.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"298 ","pages":"Article 117981"},"PeriodicalIF":6.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640578","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

Alkyl-aryl styryl-indole dyes as fluorescent imaging and theranostic probes targeting mitochondria 烷基芳基苯乙烯吲哚染料作为靶向线粒体的荧光成像和治疗探针

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-16 DOI: 10.1016/j.ejmech.2025.117974

Dijana Pavlović Saftić , Marta Domínguez-Prieto , Nicoleta Moisoi , Gea Lukić , Lucija Lulić Horvat , Jelena Puzić , Sandra Sobočanec , Marija Pinterić , Ivo Piantanida , Federico Brucoli

{"title":"Alkyl-aryl styryl-indole dyes as fluorescent imaging and theranostic probes targeting mitochondria","authors":"Dijana Pavlović Saftić , Marta Domínguez-Prieto , Nicoleta Moisoi , Gea Lukić , Lucija Lulić Horvat , Jelena Puzić , Sandra Sobočanec , Marija Pinterić , Ivo Piantanida , Federico Brucoli","doi":"10.1016/j.ejmech.2025.117974","DOIUrl":"10.1016/j.ejmech.2025.117974","url":null,"abstract":"<div><div>The development of mitochondria-targeting fluorescent compounds with theranostic potential for tumor cells remains a topic of great interest. Inspired by previously reported delocalized lipophilic cations (DLCs) based on styryl dye framework, we introduce a series of seventeen novel styrene dyes, several of which exhibit enhanced optical properties compared to their parent compounds. Most dyes display strong Stokes shifts (104–112 nm), primarily due to the indolyl chromophore, with minimal influence from other substituents. These dyes bind noncovalently to the grooves of ds-DNA/RNA with moderate affinity, responding by significantly increased fluorescence. The selected derivatives effectively penetrate living human cells, accumulating primarily in mitochondria and becoming highly fluorescent. However, their bioactivity is strongly influenced by subtle structural modifications. Notably, the introduction of a bromo-substituent to the indole ring converts a non-cytotoxic dye into the highly cytotoxic analogues <strong>10</strong><em>a</em> and <strong>10</strong><em>g</em>. Interestingly, while A549 tumor cells treated with <strong>10</strong><em>a</em> and <strong>10</strong><em>g</em> exhibit similar cytotoxic responses, the underlying mechanisms differ between normal and cancerous cells. In WI-38 cells, toxicity appeared to result from mitochondrial hyperactivation and oxidative stress, whereas in A549 cells, it is driven by mitochondrial dysfunction and metabolic collapse. This distinction underscores key differences in mitochondrial metabolism between normal and cancer cells, positioning <strong>10</strong><em>a</em> and <strong>10</strong><em>g</em> as promising lead compounds for further development as theranostic agents targeting mitochondrial vulnerabilities in cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117974"},"PeriodicalIF":6.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645680","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

Amino acid–modified chalcone derivatives with in vitro and in vivo efficacy against colon cancer 氨基酸修饰查尔酮衍生物体外和体内抗结肠癌疗效的研究

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-16 DOI: 10.1016/j.ejmech.2025.117963

Radwan El-Haggar , Reem I. Alsantali , Ahmed M. Aboshanab , Mahmoud A. Alkabbani , Yara E. Mansour , Samar S. Fatahala , Nicolas Masurier

{"title":"Amino acid–modified chalcone derivatives with in vitro and in vivo efficacy against colon cancer","authors":"Radwan El-Haggar , Reem I. Alsantali , Ahmed M. Aboshanab , Mahmoud A. Alkabbani , Yara E. Mansour , Samar S. Fatahala , Nicolas Masurier","doi":"10.1016/j.ejmech.2025.117963","DOIUrl":"10.1016/j.ejmech.2025.117963","url":null,"abstract":"<div><div>A novel series of chalcone derivatives was developed with potent anticancer activity against colon cancer. Sixteen amino acid–based compounds, incorporating phenylalanine or tryptophan to improve aqueous solubility, were evaluated by the NCI on its 60-cell line panel. Eleven showed notable growth inhibition potencies, with five exhibiting high activity, particularly against the HCT116 colon cancer cell line, and no significant toxicity on WI-38 fibroblasts. Compounds <strong>5f</strong> and <strong>5g</strong> were selected for further evaluation; both induced SubG<sub>0</sub>-G<sub>1</sub> cell cycle arrest, secondary necrosis, and upregulation of caspase-3, p53, and Bax/Bcl-2. Kinome inhibition profiling across 340 human kinases revealed that these compounds may act as PKC inhibitors, making them the first chalcones reported with such activity. In vivo, both compounds significantly reduced tumor growth, with efficacy comparable to doxorubicin. These results highlight these compounds as promising candidates for further development as anticancer agents, particularly for colon cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117963"},"PeriodicalIF":6.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640577","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

First bioconjugates in the role of highly effective human dihydroorotate dehydrogenase inhibitors: Synthesis, pharmacological, toxicological and hydrolytic stability studies of α-amino acid-modified pyrrolo[3,4-c]quinoline-1,3-dione scaffold 高效人二氢乙酸脱氢酶抑制剂的首个生物偶联物：α-氨基酸修饰吡咯[3,4-c]喹啉-1,3-二酮支架的合成、药理学、毒理学和水解稳定性研究

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-15 DOI: 10.1016/j.ejmech.2025.117972

Marina G. Dimitrijević , Cornelia Roschger , Stefanie Kehrer , Andreas Zierer , Milica G. Paunović , Ana D. Obradović , Miloš M. Matić , David Klarić , Nives Galić , Andrija Ćirić , Ljubinka Joksović , Miloš Petković , Milan D. Joksović

{"title":"First bioconjugates in the role of highly effective human dihydroorotate dehydrogenase inhibitors: Synthesis, pharmacological, toxicological and hydrolytic stability studies of α-amino acid-modified pyrrolo[3,4-c]quinoline-1,3-dione scaffold","authors":"Marina G. Dimitrijević , Cornelia Roschger , Stefanie Kehrer , Andreas Zierer , Milica G. Paunović , Ana D. Obradović , Miloš M. Matić , David Klarić , Nives Galić , Andrija Ćirić , Ljubinka Joksović , Miloš Petković , Milan D. Joksović","doi":"10.1016/j.ejmech.2025.117972","DOIUrl":"10.1016/j.ejmech.2025.117972","url":null,"abstract":"<div><div>Human dihydroorotate dehydrogenase (hDHODH) represents an attractive target for the treatment of cancer, diabetes, anti-infective and autoimmune diseases. In drug development, hDHODH inhibitors with great potency, good chemical stability and low toxicity open the broad therapeutic perspectives. Accordingly, this study identified the first bioconjugates as highly effective compounds in inhibition of hDHODH. Pyrrolo[3,4-<em>c</em>]quinoline-1,3-dione scaffold was modified with the selected α-amino acids in a new simple synthetic protocol giving the desired derivatives in good yields and high purity. Tyrosine bioconjugate <strong>4g</strong> was found to be the most potent hDHODH inhibitor (IC<sub>50</sub> = 32 nM) with an excellent cytotoxic profile on the healthy HaCaT cells and favorable lipophilicity. In the experiments with enzymes simulating oral, gastric and duodenal digestion, <strong>4g</strong> demonstrated good resistance to degradation providing a sufficient level of bioavailability. In addition, the objective of the study was to evaluate the comparative differences in toxicological effects between the <strong>4g</strong> and leflunomide on rat liver and kidney injury markers and parameters of redox homeostasis in erythrocytes. The bioactive conformation of <strong>4g</strong> on the hDHODH, determined using molecular docking, highlighted key interactions within the hDHODH binding site and provides a rational basis for further optimization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117972"},"PeriodicalIF":6.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630067","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

An optimized 2,2′-dipicolylamine-rutaecarpine quaternary ammonium derivative: targeting bacterial membrane disruption for enhanced anti-methicillin-resistant Staphylococcus aureus (MRSA) activity 优化的2,2'-二聚胺-芦桃卡松季铵衍生物：靶向细菌膜破坏增强抗耐甲氧西林金黄色葡萄球菌（MRSA）活性

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-14 DOI: 10.1016/j.ejmech.2025.117975

Ting Xu , Tingting Wang , Yue Tian , Xinhui Li , Yan Zhong , Jifeng Liu , Ruige Yang , Yong Guo

{"title":"An optimized 2,2′-dipicolylamine-rutaecarpine quaternary ammonium derivative: targeting bacterial membrane disruption for enhanced anti-methicillin-resistant Staphylococcus aureus (MRSA) activity","authors":"Ting Xu , Tingting Wang , Yue Tian , Xinhui Li , Yan Zhong , Jifeng Liu , Ruige Yang , Yong Guo","doi":"10.1016/j.ejmech.2025.117975","DOIUrl":"10.1016/j.ejmech.2025.117975","url":null,"abstract":"<div><div>The escalating threat of antibiotic resistance necessitates innovative strategies to combat multidrug-resistant pathogens. Herein, we reported the rational design of amphiphilic rutaecarpine derivatives through structural modular optimization, aiming to enhance antibacterial efficacy. A quaternary ammonium derivative <strong>IV4</strong>, bearing a 2,2′-dipicolylamine group, was found to be the most potent candidate, exhibiting remarkable activity against methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) with MIC values of 2–4 μg/mL, demonstrated rapid bactericidal kinetics, effective biofilm eradication, and exceptional plasma stability. Its superior selectivity was evidenced by low hemolytic activity (HC<sub>50</sub> > 640 μg/mL) and minimal cytotoxicity toward mammalian cells. In a murine skin infection model, <strong>IV4</strong> outperformed vancomycin in reducing bacterial load and attenuating inflammation without systemic toxicity, highlighting its strong therapeutic potential and favorable safety profile. Mechanistic studies revealed that <strong>IV4</strong> specifically binds to phosphatidylglycerol (PG) on bacterial membranes, leading to membrane disruption, excessive production of reactive oxygen species (ROS), and metabolic collapse, ultimately resulting in bacterial cell death. Collectively, these findings establish <strong>IV4</strong> as a promising membrane-targeting antibacterial agent that combines potent anti-MRSA activity with favorable biosafety, offering a novel framework for addressing antimicrobial resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117975"},"PeriodicalIF":6.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630068","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

Rational design of NAMPT-based dual inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment 基于nampt的双重抑制剂的合理设计，改善药物样和药代动力学特性，用于癌症治疗

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-12 DOI: 10.1016/j.ejmech.2025.117966

Jinke Lv , Binbin Cheng , Changshan Song

{"title":"Rational design of NAMPT-based dual inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment","authors":"Jinke Lv , Binbin Cheng , Changshan Song","doi":"10.1016/j.ejmech.2025.117966","DOIUrl":"10.1016/j.ejmech.2025.117966","url":null,"abstract":"<div><div>While PD-1/PD-L1 immunotherapy has demonstrated significant clinical efficacy, current small-molecule inhibitors are limited by suboptimal oral bioavailability (<em>F</em> < 10 %) due to unfavorable physicochemical properties. To address this challenge, we developed bifunctional inhibitors that simultaneously target NAMPT (nicotinamide phosphoribosyltransferase) and PD-L1, leveraging NAMPT's critical role in immunometabolic reprogramming. The lead compound <strong>T8</strong> exhibited potent dual-target inhibition, with an IC<sub>50</sub> of 63 nM against PD-L1 and 0.582 μM against NAMPT, along with superior pharmacokinetic properties, including oral bioavailability of 78.8 % in mice and 64.4 % in rats. In B16–F10 melanoma models, <strong>T8</strong> achieved enhanced tumor growth inhibition (TGI = 40.1 %) compared to anti-PD-L1 antibodies (28.2 %), mechanistically attributed to the activation of the tumor immune microenvironment. This study identifies <strong>T8</strong> as a potent orally bioavailable dual PD-L1/NAMPT inhibitor, thereby validating the co-targeting of NAMPT as a transformative strategy for cancer immunotherapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117966"},"PeriodicalIF":6.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611438","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 potent, selective human TLR1/2 agonists: N-quinoline-N'-(thiophen-2-yl)thiourea analogs for potential cancer immunotherapy 发现有效的，选择性的人类TLR1/2激动剂：n-喹啉- n '-（噻吩-2-基）硫脲类似物用于潜在的癌症免疫治疗

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-12 DOI: 10.1016/j.ejmech.2025.117968

Xiaoshan Zeng , Qiuyue Fu , Ruilian Liao , Hua Mei , Lan Huang , Zhibo Zhu , Kui Cheng , Zhipeng Chen

{"title":"Discovery of potent, selective human TLR1/2 agonists: N-quinoline-N'-(thiophen-2-yl)thiourea analogs for potential cancer immunotherapy","authors":"Xiaoshan Zeng , Qiuyue Fu , Ruilian Liao , Hua Mei , Lan Huang , Zhibo Zhu , Kui Cheng , Zhipeng Chen","doi":"10.1016/j.ejmech.2025.117968","DOIUrl":"10.1016/j.ejmech.2025.117968","url":null,"abstract":"<div><div>TLR2 agonists represent promising cancer immunotherapeutic due to their unique combination of potency and safety. <strong>SMU-C68</strong>, a human TLR1/2 specific small molecule agonist was identified, exhibiting a remarkable four-fold increase in biological activity compared to previously reported <strong>SMU-C80</strong> with enhanced aqueous solubility. The cellular and protein level results confirmed that <strong>SMU-C68</strong> facilitated the dimerization of TLR1 and TLR2 proteins, leading to the specific activation of TLR1/2 heterodimers. Upon activation, TLR2 recruited the adaptor protein MyD88, initiating downstream NF-<em>κ</em>B signaling pathway. Moreover, treatment with <strong>SMU-C68</strong> induced the release of pro-inflammatory factors, such as TNF-<em>α</em> and IL-1<em>β</em>, in human PBMC cells. Notably, <strong>SMU-C68</strong> exhibited good selectivity towards human species and showed minimal effects on murine cells. Furthermore, <em>in vitro</em> co-culture experiments demonstrated that <strong>SMU-C68</strong> exerted a positive influence on immune cell activation and tumor cell apoptosis. These findings strongly emphasize the potential of <strong>SMU-C68</strong> in modulating immune responses and eliciting anti-tumor activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117968"},"PeriodicalIF":6.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611465","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 novel and potent antiplatelet thiol prodrug CG-0255 一种新型有效抗血小板巯基前药CG-0255的发现

IF 6 2区医学

European Journal of Medicinal Chemistry Pub Date : 2025-07-12 DOI: 10.1016/j.ejmech.2025.117973

Hao Wu, Kai Hou, Xiaowu Chen, Xiubo Tang, Wenyuan Fan, Changliang Lu, Yuanchao Zhang, Ziqiang Gu, Gongxin He

{"title":"Discovery of a novel and potent antiplatelet thiol prodrug CG-0255","authors":"Hao Wu, Kai Hou, Xiaowu Chen, Xiubo Tang, Wenyuan Fan, Changliang Lu, Yuanchao Zhang, Ziqiang Gu, Gongxin He","doi":"10.1016/j.ejmech.2025.117973","DOIUrl":"10.1016/j.ejmech.2025.117973","url":null,"abstract":"<div><div>A series of novel thiol prodrugs based on clopidogrel active metabolite <strong>H4</strong> were conceived and synthesized as a new generation of antiplatelet agents. The prodrugs are capable of being rapidly converted to <strong>H4</strong> through fast one-step hydrolysis catalyzed by carboxylesterases, thus potentially overcoming clopidogrel resistance and many other issues caused by the reliance of clopidogrel on cytochrome P-450 (CYP)-mediated oxidative bioactivation. One of the thiol prodrugs, <strong>CG-0255</strong>, was selected for further development. <strong>CG-0255</strong> exhibited excellent pharmacokinetic and pharmacodynamic properties suitable for being developed as a once daily oral antiplatelet drug. In addition, <strong>CG-0255</strong> possessed adequate solubility and chemical stability capable of being formulated as an intravenous formulation, expanding its uses into surgical or emergency settings where intravenous administration is more desired. <strong>CG-0255</strong> is the first P2Y<sub>12</sub> inhibitor available in both intravenous and oral formulation, showing several advantages, such as rapid onset of action, low risk of drug-drug interaction, and an expected reduction in individual variation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117973"},"PeriodicalIF":6.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611440","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