Pub Date : 2026-01-20DOI: 10.1016/j.ejmech.2026.118590
Yiman Wang , Chen Ma , Xinya Liu , Junkai Cheng , Dan Zhu , Peng Liu , Peng Qi , Xiankai Li , Jian Gu , Qin Wang
Epigenetic modifications, such as DNA methylation, histone methylation, and RNA methylation, dynamically regulate gene transcription and play critical roles in cellular differentiation, development, and disease, especially cancer. Inhibitors targeting the enzymes responsible for these modifications have emerged as promising cancer therapies. For instance, DNMT inhibitors (e.g., azacitidine, decitabine) can reactivate tumor suppressor genes via demethylation; HMT inhibitors like tazemetostat and EPZ-5676 modulate chromatin structure to exert anti-tumor effects; and RNA methyltransferase inhibitors such as STM2457 disrupt RNA metabolism to suppress tumor growth. Despite encouraging preclinical and clinical results, challenges including toxicity and drug resistance remain obstacles to broader clinical application. This review summarizes recent advances in epigenetic inhibitor development to support the design of safer and more effective targeted cancer therapies.
{"title":"Epigenetic enzyme inhibitors targeting DNA, histone, and RNA methylation: Mechanisms and therapeutic applications in cancer","authors":"Yiman Wang , Chen Ma , Xinya Liu , Junkai Cheng , Dan Zhu , Peng Liu , Peng Qi , Xiankai Li , Jian Gu , Qin Wang","doi":"10.1016/j.ejmech.2026.118590","DOIUrl":"10.1016/j.ejmech.2026.118590","url":null,"abstract":"<div><div>Epigenetic modifications, such as DNA methylation, histone methylation, and RNA methylation, dynamically regulate gene transcription and play critical roles in cellular differentiation, development, and disease, especially cancer. Inhibitors targeting the enzymes responsible for these modifications have emerged as promising cancer therapies. For instance, DNMT inhibitors (e.g., azacitidine, decitabine) can reactivate tumor suppressor genes via demethylation; HMT inhibitors like tazemetostat and EPZ-5676 modulate chromatin structure to exert anti-tumor effects; and RNA methyltransferase inhibitors such as STM2457 disrupt RNA metabolism to suppress tumor growth. Despite encouraging preclinical and clinical results, challenges including toxicity and drug resistance remain obstacles to broader clinical application. This review summarizes recent advances in epigenetic inhibitor development to support the design of safer and more effective targeted cancer therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118590"},"PeriodicalIF":5.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005743","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}
Pub Date : 2026-01-20DOI: 10.1016/j.ejmech.2026.118592
Yu Tong, Nuo Cheng, Chun Guan, Yue Wu, Yi Gao, Shihao Liu, Cong Wang, Can Zhang
{"title":"Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on phenyl-indole scaffold","authors":"Yu Tong, Nuo Cheng, Chun Guan, Yue Wu, Yi Gao, Shihao Liu, Cong Wang, Can Zhang","doi":"10.1016/j.ejmech.2026.118592","DOIUrl":"https://doi.org/10.1016/j.ejmech.2026.118592","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014767","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}
Pub Date : 2026-01-20DOI: 10.1016/j.ejmech.2026.118596
Woo Hyun Park
Malignancy's profound dependence on mitochondrial metabolism establishes the organelle as a paramount therapeutic target. This review offers a comprehensive analysis of Antimycin A (AMA), a mitochondrial complex III inhibitor, framing it as a potent, multi-pronged anti-cancer agent. While AMA primarily disrupts oxidative phosphorylation (OXPHOS)—triggering a cascade of adenosine triphosphate (ATP) depletion, massive reactive oxygen species (ROS) surges, and subsequent apoptosis—its therapeutic potential extends significantly to non-canonical functions crucial for countering adaptive resilience. Specifically, AMA acts as a Bcl-2 homology 3 (BH3) mimetic by directly inhibiting B-cell lymphoma-extra large (Bcl-xL) and induces ROS-mediated proteasomal degradation of the c-Myc oncoprotein. Additionally, it effectively targets chemoresistant cancer stem cells (CSCs) by suppressing Wnt/β-catenin signaling. By juxtaposing its powerful anti-neoplastic activities with pharmacological limitations such as systemic toxicity, this paper evaluates ongoing strategies to develop safer, clinically viable analogues. Ultimately, AMA is presented not merely as an experimental tool, but as a pivotal lead compound whose mechanisms illuminate critical vulnerabilities in cancer, providing a strategic blueprint for the future of mitochondria-targeted oncology.
{"title":"The mitochondrial gambit: Re-evaluating Antimycin A as a multi-pronged anti-cancer agent","authors":"Woo Hyun Park","doi":"10.1016/j.ejmech.2026.118596","DOIUrl":"10.1016/j.ejmech.2026.118596","url":null,"abstract":"<div><div>Malignancy's profound dependence on mitochondrial metabolism establishes the organelle as a paramount therapeutic target. This review offers a comprehensive analysis of Antimycin A (AMA), a mitochondrial complex III inhibitor, framing it as a potent, multi-pronged anti-cancer agent. While AMA primarily disrupts oxidative phosphorylation (OXPHOS)—triggering a cascade of adenosine triphosphate (ATP) depletion, massive reactive oxygen species (ROS) surges, and subsequent apoptosis—its therapeutic potential extends significantly to non-canonical functions crucial for countering adaptive resilience. Specifically, AMA acts as a Bcl-2 homology 3 (BH3) mimetic by directly inhibiting B-cell lymphoma-extra large (Bcl-xL) and induces ROS-mediated proteasomal degradation of the c-Myc oncoprotein. Additionally, it effectively targets chemoresistant cancer stem cells (CSCs) by suppressing Wnt/β-catenin signaling. By juxtaposing its powerful anti-neoplastic activities with pharmacological limitations such as systemic toxicity, this paper evaluates ongoing strategies to develop safer, clinically viable analogues. Ultimately, AMA is presented not merely as an experimental tool, but as a pivotal lead compound whose mechanisms illuminate critical vulnerabilities in cancer, providing a strategic blueprint for the future of mitochondria-targeted oncology.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118596"},"PeriodicalIF":5.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014763","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}
Pub Date : 2026-01-20DOI: 10.1016/j.ejmech.2026.118606
Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes injuries in the gastrointestinal mucosa. Proton pump inhibitors are the most common drugs prescribed to decrease upper gastrointestinal side effects caused by NSAIDs. However, they worsen the lower GI injuries caused by NSAIDs and do not directly promote restitution of the epithelial mucosa. Focal adhesion kinase (FAK) is essential in wound healing and epithelial sheet migration, making it an attractive pharmacological target. We have designed, synthesized, and evaluated a series of novel, specific FAK activators that increase FAK phosphorylation at Tyr-397 and promote mucosal healing in a Caco-2 model. We found that novel analogs 10bHCl, 10kHCl, and our original lead 5aHCl are preclinical candidates for further studies towards mucosal wound healing. For lead 5aHCl, which had previously shown healing in a mouse model, we performed a pharmacokinetic study. There are currently no therapeutics that promote mucosal healing, and no specific FAK activators beyond our work.
{"title":"Discovery of Focal Adhesion Kinase (FAK) activators to promote intestinal mucosal healing","authors":"Ricardo Gallardo-Macias , Qinggang Wang , Ahmed Adham Raafat Elsayed , Guiming Liu , Henry L. Wong , Gunda I. Georg , Marc D. Basson , Vadim J. Gurvich","doi":"10.1016/j.ejmech.2026.118606","DOIUrl":"10.1016/j.ejmech.2026.118606","url":null,"abstract":"<div><div>Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) causes injuries in the gastrointestinal mucosa. Proton pump inhibitors are the most common drugs prescribed to decrease upper gastrointestinal side effects caused by NSAIDs. However, they worsen the lower GI injuries caused by NSAIDs and do not directly promote restitution of the epithelial mucosa. Focal adhesion kinase (FAK) is essential in wound healing and epithelial sheet migration, making it an attractive pharmacological target. We have designed, synthesized, and evaluated a series of novel, specific FAK activators that increase FAK phosphorylation at Tyr-397 and promote mucosal healing in a Caco-2 model. We found that novel analogs <strong>10bHCl</strong>, <strong>10kHCl,</strong> and our original lead <strong>5aHCl</strong> are preclinical candidates for further studies towards mucosal wound healing. For lead <strong>5aHCl</strong>, which had previously shown healing in a mouse model, we performed a pharmacokinetic study. There are currently no therapeutics that promote mucosal healing, and no specific FAK activators beyond our work.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118606"},"PeriodicalIF":5.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014770","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}
Pub Date : 2026-01-19DOI: 10.1016/j.ejmech.2026.118570
Daxing Shi , Xianan Liu , Jingyuan Huang , Chenxiao Li , Qiansong Chen , Feilong Zhou , Xing Chen
Dipeptidyl peptidase I (DPP-I) mediates the processing and maturation of various serine proteases by cleaving dipeptide structures from N-terminus of zymogen proteins. This process enables DPP-I to participate in inflammatory cascades, thereby establishing it as a key therapeutic target for inflammatory diseases. Here, starting from a serendipitously discovered molecular block with weak DPP-I inhibitory activity, a series of tryptophan analogs were designed and synthesized. Following biological activity evaluation, compound C10b as a potent DPP-I inhibitor was identified. Through structure-activity relationship and docking analyses, the binding mode and key interactions were elucidated. In vitro results confirmed C10b could bind to and inhibit intracellular DPP-I activity, and further down-regulate the activity and expression levels of downstream neutrophil serine proteases, while exhibiting excellent anti-inflammatory activity and regulating the secretion of various inflammatory factors. In vivo results demonstrated C10b possessed acceptable toxicity and good pharmacodynamic activity. In the adjuvant-induced arthritis model in rats, C10b exerted an anti-inflammatory effect and reversed joint inflammation and tissue damage. Collectively, as a novel DPP-I inhibitor, C10b exhibits nice anti-inflammatory activity and considerable potential for further development, which supports its application in development of therapeutic agent for neutrophil-associated inflammatory diseases.
{"title":"Design and anti-inflammatory activity evaluation of tryptophan analogs as novel dipeptidyl peptidase I inhibitors","authors":"Daxing Shi , Xianan Liu , Jingyuan Huang , Chenxiao Li , Qiansong Chen , Feilong Zhou , Xing Chen","doi":"10.1016/j.ejmech.2026.118570","DOIUrl":"10.1016/j.ejmech.2026.118570","url":null,"abstract":"<div><div>Dipeptidyl peptidase I (DPP-I) mediates the processing and maturation of various serine proteases by cleaving dipeptide structures from N-terminus of zymogen proteins. This process enables DPP-I to participate in inflammatory cascades, thereby establishing it as a key therapeutic target for inflammatory diseases. Here, starting from a serendipitously discovered molecular block with weak DPP-I inhibitory activity, a series of tryptophan analogs were designed and synthesized. Following biological activity evaluation, compound <strong>C10b</strong> as a potent DPP-I inhibitor was identified. Through structure-activity relationship and docking analyses, the binding mode and key interactions were elucidated. <em>In vitro</em> results confirmed <strong>C10b</strong> could bind to and inhibit intracellular DPP-I activity, and further down-regulate the activity and expression levels of downstream neutrophil serine proteases, while exhibiting excellent anti-inflammatory activity and regulating the secretion of various inflammatory factors. <em>In vivo</em> results demonstrated <strong>C10b</strong> possessed acceptable toxicity and good pharmacodynamic activity. In the adjuvant-induced arthritis model in rats, <strong>C10b</strong> exerted an anti-inflammatory effect and reversed joint inflammation and tissue damage. Collectively, as a novel DPP-I inhibitor, <strong>C10b</strong> exhibits nice anti-inflammatory activity and considerable potential for further development, which supports its application in development of therapeutic agent for neutrophil-associated inflammatory diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118570"},"PeriodicalIF":5.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001184","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}
Pub Date : 2026-01-19DOI: 10.1016/j.ejmech.2026.118595
Shangde Liu , Tianlei Han , Zhenyu Zhang , Hui Yu , Albert A. Antolin , Huabin Hu
ATP-competitive kinase inhibitors represent one of the most successful modalities in targeted therapy, yet their discovery has historically relied on a narrow repertoire of hinge-binding motifs. Here, we report a large-scale structural analysis of 4370 kinase–ligand complexes spanning 289 human protein kinases, providing the most comprehensive publicly available catalogue of hinge-binding scaffolds to date. Systematic extraction and consolidation identified 846 unique hinge binders, enabling quantitative assessment of their frequency, promiscuity, and residue interactions across the kinome. The analysis reveals that hinge binders remain predominantly planar heteroaromatic chemotypes, and that progress over the past three decades has largely involved incremental optimization of these limited motifs rather than exploration of sp3-enriched scaffolds. Novel opportunities for chemical innovation were identified through noncanonical interactions, such as halogen bonding, as well as through conformationally restricted designs, including macrocycles to generate sp3-enriched hinge-binding moieties. Although limited in number, these examples demonstrate that nonplanar chemotypes can achieve hinge engagement comparable to that of rigid planar binders while substantially expanding the accessible chemical space of kinase inhibitors. Collectively, this work delineates the structural landscape of kinase hinge binders and provides a hinge-binding resource to enable scaffold hopping and focused library design, while identifying opportunities for the discovery of next-generation ATP-competitive kinase inhibitors within a highly competitive therapeutic space.
{"title":"Charting the evolving landscape of kinase hinge-binding chemotypes beyond flatland: a systematic analysis and opportunities for sp3-rich binders","authors":"Shangde Liu , Tianlei Han , Zhenyu Zhang , Hui Yu , Albert A. Antolin , Huabin Hu","doi":"10.1016/j.ejmech.2026.118595","DOIUrl":"10.1016/j.ejmech.2026.118595","url":null,"abstract":"<div><div>ATP-competitive kinase inhibitors represent one of the most successful modalities in targeted therapy, yet their discovery has historically relied on a narrow repertoire of hinge-binding motifs. Here, we report a large-scale structural analysis of 4370 kinase–ligand complexes spanning 289 human protein kinases, providing the most comprehensive publicly available catalogue of hinge-binding scaffolds to date. Systematic extraction and consolidation identified 846 unique hinge binders, enabling quantitative assessment of their frequency, promiscuity, and residue interactions across the kinome. The analysis reveals that hinge binders remain predominantly planar heteroaromatic chemotypes, and that progress over the past three decades has largely involved incremental optimization of these limited motifs rather than exploration of sp<sup>3</sup>-enriched scaffolds. Novel opportunities for chemical innovation were identified through noncanonical interactions, such as halogen bonding, as well as through conformationally restricted designs, including macrocycles to generate sp<sup>3</sup>-enriched hinge-binding moieties. Although limited in number, these examples demonstrate that nonplanar chemotypes can achieve hinge engagement comparable to that of rigid planar binders while substantially expanding the accessible chemical space of kinase inhibitors. Collectively, this work delineates the structural landscape of kinase hinge binders and provides a hinge-binding resource to enable scaffold hopping and focused library design, while identifying opportunities for the discovery of next-generation ATP-competitive kinase inhibitors within a highly competitive therapeutic space.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118595"},"PeriodicalIF":5.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146001183","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}
Pub Date : 2026-01-17DOI: 10.1016/j.ejmech.2026.118593
Qing-Song Chen, Jian-Hua Liang
Although PROTAC technology has revolutionized drug discovery by enabling the degradation of previously undruggable proteins, the clinical translation of traditional PROTACs has been hindered by limitations in E3 ligase availability, suboptimal drug-like properties, and a narrow target scope. In recent years, the emergence of diversified novel PROTAC design strategies, such as chaperone-mediated PROTAC (CHAMP), mini-PROTAC, covalent PROTAC, HyTTD, and pro-PROTAC, has elevated the technology to new heights, accelerating its clinical advancement. However, a critical question remains: How can we select the most appropriate strategy among these options? We summarized and analyzed their strengths and limitations, covering optimization and expansion of E3 ligase-dependent and E3 ligase-independent degrader strategies, undruggable targets degrader strategies, linker optimization and expansion strategies, and pro-PROTAC strategies. Furthermore, we provide guidance on selecting appropriate strategies based on specific target characteristics for designing effective PROTAC, with the aim of facilitating the translation of these innovative approaches toward clinical applications.
{"title":"Diversified design strategies for small-molecule PROTACs: How do we select?","authors":"Qing-Song Chen, Jian-Hua Liang","doi":"10.1016/j.ejmech.2026.118593","DOIUrl":"10.1016/j.ejmech.2026.118593","url":null,"abstract":"<div><div>Although PROTAC technology has revolutionized drug discovery by enabling the degradation of previously undruggable proteins, the clinical translation of traditional PROTACs has been hindered by limitations in E3 ligase availability, suboptimal drug-like properties, and a narrow target scope. In recent years, the emergence of diversified novel PROTAC design strategies, such as chaperone-mediated PROTAC (CHAMP), mini-PROTAC, covalent PROTAC, HyTTD, and pro-PROTAC, has elevated the technology to new heights, accelerating its clinical advancement. However, a critical question remains: How can we select the most appropriate strategy among these options? We summarized and analyzed their strengths and limitations, covering optimization and expansion of E3 ligase-dependent and E3 ligase-independent degrader strategies, undruggable targets degrader strategies, linker optimization and expansion strategies, and pro-PROTAC strategies. Furthermore, we provide guidance on selecting appropriate strategies based on specific target characteristics for designing effective PROTAC, with the aim of facilitating the translation of these innovative approaches toward clinical applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118593"},"PeriodicalIF":5.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995780","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}
Pub Date : 2026-01-17DOI: 10.1016/j.ejmech.2026.118591
Siyuan Tang , Jiangwen Gui , Yingjie Lan , Panwen Liu , Yuliang Lin , Meng Sun , Shaoliang Duan , Chao Zhang , Denggao Zhang , Min Liu , Xiaobo Mai , Jiaqi Tan , Zhiwen Wang , Jinggen Liu , Liming Shao , Wei Fu , Yujun Wang , Wei Li
4,5-Epoxymorphinan derivatives represent a privileged chemotype among opioid ligands, with well-established clinical utility, and continue to serve as a widely used scaffold for the development of novel opioid-like therapeutics. This work describes the design and synthesis of a series of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives and identifies compound 8a as a structurally optimized KOR agonist with high KOR affinity, pronounced MOR/KOR and DOR/KOR subtype selectivity, and marked G-protein bias. In vivo, compound 8a exhibited robust, dose-dependent antinociceptive activity in both the hot-plate and abdominal constriction assays, with ED50 values of 8.2 and 0.5 mg/kg, respectively. Nevertheless, the emergence of motor impairment and aversive effects at behaviorally relevant doses underscores a critical limitation of relying solely on cell-based G-protein bias as a predictor of improved central nervous system safety for KOR agonists.
{"title":"Structure-activity relationship of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives as G-protein-biased KOR-selective agonists","authors":"Siyuan Tang , Jiangwen Gui , Yingjie Lan , Panwen Liu , Yuliang Lin , Meng Sun , Shaoliang Duan , Chao Zhang , Denggao Zhang , Min Liu , Xiaobo Mai , Jiaqi Tan , Zhiwen Wang , Jinggen Liu , Liming Shao , Wei Fu , Yujun Wang , Wei Li","doi":"10.1016/j.ejmech.2026.118591","DOIUrl":"10.1016/j.ejmech.2026.118591","url":null,"abstract":"<div><div>4,5-Epoxymorphinan derivatives represent a privileged chemotype among opioid ligands, with well-established clinical utility, and continue to serve as a widely used scaffold for the development of novel opioid-like therapeutics. This work describes the design and synthesis of a series of <em>N</em>-cyclopropylmethyl-7α-(<em>m</em>-methylaminophenyl)-6,14-<em>endo</em>ethano-northebaine derivatives and identifies compound <strong>8a</strong> as a structurally optimized KOR agonist with high KOR affinity, pronounced MOR/KOR and DOR/KOR subtype selectivity, and marked G-protein bias. <em>In vivo</em>, compound <strong>8a</strong> exhibited robust, dose-dependent antinociceptive activity in both the hot-plate and abdominal constriction assays, with ED<sub>50</sub> values of 8.2 and 0.5 mg/kg, respectively. Nevertheless, the emergence of motor impairment and aversive effects at behaviorally relevant doses underscores a critical limitation of relying solely on cell-based G-protein bias as a predictor of improved central nervous system safety for KOR agonists.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"306 ","pages":"Article 118591"},"PeriodicalIF":5.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995782","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}
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