Journal of Medicinal Chemistry最新文献

Design of a Fluorescence Polarization Probe for Enterovirus 2C Proteins. 肠病毒2C蛋白荧光极化探针的设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-21 DOI: 10.1021/acs.jmedchem.5c01219

Kan Li,Hiwot A Demssie,Jun Wang

引用次数: 0

3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer’s Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo 3-羟基喹啉-2- 1作为铁中毒和单胺氧化酶B的双重抑制剂：体内降低阿尔茨海默病相关淀粉样前体蛋白和过度磷酸化的Tau

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-21 DOI: 10.1021/acs.jmedchem.5c00502

Yangjing Lv, Xiaoxin Song, Jiayan He, Xiaomeng Jiang, Liwen Lu, Miaoliang Fan, Zili Guo, Changjun Zhang, Yuanyuan Xie

{"title":"3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer’s Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo","authors":"Yangjing Lv, Xiaoxin Song, Jiayan He, Xiaomeng Jiang, Liwen Lu, Miaoliang Fan, Zili Guo, Changjun Zhang, Yuanyuan Xie","doi":"10.1021/acs.jmedchem.5c00502","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00502","url":null,"abstract":"The challenges in the current treatment landscape for Alzheimer’s disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent neuronal injury through ferroptosis. Additionally, overexpression of monoamine oxidase B (MAO-B) induces oxidative stress and decreases cognitive function. In this study, we presented the novel dual inhibitors of ferroptosis and MAO-B for AD management, aiming to address both the symptomatic and neurodegenerative aspects of this disease. Compound 21d emerged as a promising candidate, exhibiting potent and selective MAO-B inhibitory activity (IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis activity through modulation of the iron metabolic pathway and GSH-GPX4 axis in vitro. Importantly, 21d normalized cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse model and reduced levels of AD-related proteins, including amyloid precursor protein and phosphorylated Tau protein, in the brains of AD mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"608 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Small-Molecule Strategies against Human Adenoviruses: Progress, Challenges, and Future Perspectives 对抗人类腺病毒的小分子策略：进展、挑战和未来展望

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-21 DOI: 10.1021/acs.jmedchem.5c00868

Jingwen Huo, Haiying Chen, Xinhui Qiu, Ge Wang, Javier Sánchez-Céspedes, Kuancheng Liu, Jia Zhou, Jimin Xu

{"title":"Small-Molecule Strategies against Human Adenoviruses: Progress, Challenges, and Future Perspectives","authors":"Jingwen Huo, Haiying Chen, Xinhui Qiu, Ge Wang, Javier Sánchez-Céspedes, Kuancheng Liu, Jia Zhou, Jimin Xu","doi":"10.1021/acs.jmedchem.5c00868","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00868","url":null,"abstract":"Human adenoviruses (HAdVs) present a significant health threat, particularly to immunocompromised individuals, where infections can progress to severe, life-threatening disease. Despite their clinical impact, no FDA-approved antiviral therapies specifically target HAdV infection. Current treatments, such as off-label cidofovir, are limited by nephrotoxicity, poor oral bioavailability, and resistance concerns, underscoring the urgent need for safer and more effective alternatives. This perspective critically evaluates recent advances in small-molecule anti-HAdV drug development, highlighting promising molecular scaffolds, innovative screening methodologies, and host-targeted strategies. Beyond repurposed drugs, we emphasize the importance of exploring diverse chemical spaces and integrating structure-based design with high-throughput phenotypic screening. By integrating insights from medicinal chemistry, virology, and pharmacology perspectives, the relevant challenges and strategic considerations to optimize anti-HAdV drug discovery and accelerate the translation of next-generation therapeutics into clinical application are discussed.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Identification of Cannabigerol-Derived Dual CB2 Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities. 具有抗炎镇痛活性的大麻酚衍生双CB2受体激动剂和TRPM8拮抗剂的鉴定。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-20 DOI: 10.1021/acs.jmedchem.4c03220

Wenjiao Yang,Haiguo Sun,Jing Ji,Hai Chen,Jiaxin Cheng,Zhengtao Hu,Xudong Gong,Qi Liu,Su Peng,Jin Suo,Tianwen Hu,Guanghui Tian,Jingshan Shen,Qiongqiong Hou,Yang He,Haji Akber Aisa

{"title":"Identification of Cannabigerol-Derived Dual CB2 Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities.","authors":"Wenjiao Yang,Haiguo Sun,Jing Ji,Hai Chen,Jiaxin Cheng,Zhengtao Hu,Xudong Gong,Qi Liu,Su Peng,Jin Suo,Tianwen Hu,Guanghui Tian,Jingshan Shen,Qiongqiong Hou,Yang He,Haji Akber Aisa","doi":"10.1021/acs.jmedchem.4c03220","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03220","url":null,"abstract":"Emerging evidence suggests that compounds possessing both CB2 receptor (CB2R) agonist and TRPM8 antagonist activities may offer effective pain relief while minimizing the severe side effects commonly associated with current analgesics. In this study, we designed and synthesized a series of novel cannabigerol (CBG) derivatives with the goal of identifying potent dual ligands that act as both CB2R agonists and TRPM8 antagonists. Structure-activity relationship studies revealed that the introduction of an amide group at the C-2 position or alkylation at the C-3 position of CBG is essential for enhancing CB2R agonistic and TRPM8 antagonistic activities. CBG amides 2a and 6b exhibited dual activity as CB2R agonists and TRPM8 antagonists, displaying notable anti-inflammatory and analgesic efficacy alongside a favorable safety profile. Notably, compound 8b, a prodrug of 6b, demonstrated improved oral plasma exposure and enhanced analgesic effects in mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Potent, Selective, and Multiple His435 Mutation-Sensitive Thyroid Hormone Receptor β Agonist. 一种有效的、选择性的、多重His435突变敏感甲状腺激素受体β激动剂的发现。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-20 DOI: 10.1021/acs.jmedchem.5c00164

Qiu Li,Benqiang Yao,Shiting Zhao,Zhou Lu,Xishan Wu,Zhifang Lu,Tong Wu,Junhua Li,Xiaoshan Chen,Zhiming Chen,Cheng Zhang,Donghai Wu,Yan Zhang,Qiuping Xiang,Yong Li,Yong Xu

{"title":"Discovery of a Potent, Selective, and Multiple His435 Mutation-Sensitive Thyroid Hormone Receptor β Agonist.","authors":"Qiu Li,Benqiang Yao,Shiting Zhao,Zhou Lu,Xishan Wu,Zhifang Lu,Tong Wu,Junhua Li,Xiaoshan Chen,Zhiming Chen,Cheng Zhang,Donghai Wu,Yan Zhang,Qiuping Xiang,Yong Li,Yong Xu","doi":"10.1021/acs.jmedchem.5c00164","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00164","url":null,"abstract":"Beyond selectivity concerns for thyroid hormone receptor β (THR-β) agonists, intolerance to the His435 mutation remains a challenge. Following our previous study, we performed detailed modifications on the 7-position of isoquinoline, specifically targeting the hydrophobic region of the THR-β ligand-binding pocket (LBP). This led to the identification of compound 15n, which showed potent THR-β agonistic activity (EC50: 3.2 nM), moderately selectivity (∼10-fold), and good activation of multiple His435 mutants (EC50: 134.2 nM to 515.5 nM). Co-crystal structures revealed that the introduction of small-volume groups into the hydrophobic pocket of THR-β almost did not significantly displace helix 11 or helix 3, explaining why 15n can activate multiple His435 mutants simultaneously. Multiple experiments confirmed that 15n exhibits excellent lipid metabolism, safety, and pharmacokinetic properties. Together, 15n emerges as a potent, selective, and His435 mutation-sensitive THR-β agonist, offering potential for treating dyslipidemia, metabolic dysfunction-associated steatohepatitis (MASH), or resistance to thyroid hormone (RTH).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Small-Molecule Orthopoxvirus Resolvase Inhibitors with Antiviral Activity. 具有抗病毒活性的小分子正痘病毒分解抑制剂的发现。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-19 DOI: 10.1021/acs.jmedchem.5c00019

Jacob P Mahoney,Samuel Offei,Anil Pant,Ziyue Wang,Benjamin Weiner,Lulu Yin,Won Hee Ryu,Roshan Katekar,Jessica M Williams,Hideki Aihara,Zhilong Yang,Zhengqiang Wang

{"title":"Discovery of Small-Molecule Orthopoxvirus Resolvase Inhibitors with Antiviral Activity.","authors":"Jacob P Mahoney,Samuel Offei,Anil Pant,Ziyue Wang,Benjamin Weiner,Lulu Yin,Won Hee Ryu,Roshan Katekar,Jessica M Williams,Hideki Aihara,Zhilong Yang,Zhengqiang Wang","doi":"10.1021/acs.jmedchem.5c00019","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00019","url":null,"abstract":"Poxvirus genome replication and viral maturation require a Holliday junction resolvase. Genetic evidence suggests that targeting the virally encoded resolvase could offer a novel antiviral approach against orthopoxviruses. However, orthopoxvirus resolvases have not been characterized biochemically and pharmacologically, and inhibitors remain unknown. Herein, we have developed and optimized the first in vitro assay directly measuring the activity of mpox virus (MPXV) resolvase (Mpr) and vaccinia virus (VACV) resolvase (A22). The subsequent pilot screen of an in-house compound library using this assay identified multiple inhibitors, each inhibiting both Mpr and A22, and conferring antiviral activity against VACV. Computationally, these inhibitors docked well into the active site of an AlphaFold-generated Mpr structural model. The assay developed herein and the inhibitors identified and characterized provide a valuable platform for developing compounds as broad-spectrum antiviral drug leads against MPXV and other potentially emerging orthopoxviruses, and as probes to investigate the functions of Mpr.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A Lysosome-Targeted Iridium(III) Complex Inducing Pyroptosis for Enhanced Sonodynamic Therapy of Colorectal Cancer. 一种溶酶体靶向铱（III）复合物诱导焦亡增强声动力治疗结直肠癌。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-19 DOI: 10.1021/acs.jmedchem.5c01106

Lingting Guan,Siyi Tao,Xufeng Lu,Ying Jiang,Kuang Xu,Jie Peng,Wei Shen,Ganhua Guo,Zhifa Shen,Jiaxi Ru

{"title":"A Lysosome-Targeted Iridium(III) Complex Inducing Pyroptosis for Enhanced Sonodynamic Therapy of Colorectal Cancer.","authors":"Lingting Guan,Siyi Tao,Xufeng Lu,Ying Jiang,Kuang Xu,Jie Peng,Wei Shen,Ganhua Guo,Zhifa Shen,Jiaxi Ru","doi":"10.1021/acs.jmedchem.5c01106","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01106","url":null,"abstract":"Sonodynamic therapy (SDT) is a promising noninvasive cancer treatment due to its superior tissue penetration depth compared to phototherapy. Herein, we developed a lysosome-targeted cyclometalated Ir(III) complex (Lyso-Ir) as a highly efficient sonosensitizer and sonoredox catalyst for enhanced SDT against colorectal cancer. Lyso-Ir outperforms [Ru(bpy)3]Cl2 in both 1O2 generation (2.74-fold) and sonocatalytic oxidation of NADH (2.92-fold). Notably, under lysosomal pH conditions, its performance is significantly enhanced with improvements of 22.9-fold (1O2 generation) and 7.5-fold (NADH oxidation) over neutral physiological conditions, respectively. This is advantageous for tumor therapy, given the inherent weak acidity of lysosomes and the tumor microenvironment. Notably, Lyso-Ir could target the lysosome, generate 1O2 under ultrasound irradiation, induce lysosomal membrane permeabilization, activate caspase-3, trigger GSDME cleavage, and ultimately lead to pyroptosis. This is highly advantageous for overcoming apoptosis resistance and activating antitumor immune responses. This work provides a promising new strategy for the treatment of deep-seated colorectal tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Enhancing Selectivity and Potency of SNAr Covalent Inhibitors of NADPH Oxidase Enzymes. 提高NADPH氧化酶SNAr共价抑制剂的选择性和效力。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-19 DOI: 10.1021/acs.jmedchem.5c01272

Blessing C Ogboo,Kishan B Patel,Marta Massari,Sara Marchese,Joana Reis,Emily J Joyce,Miao-Chong J Lin,Johnathan D Rabb,Omobolanle A Abidakun,Qing Lin,Albert van der Vliet,Andrea Mattevi,David E Heppner

引用次数: 0

Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq 一种基于色胺的可见光可切换5-HT2AR配体的设计、合成和体外表征，该配体对β-抑制素的作用优于Mini-Gq

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-18 DOI: 10.1021/acs.jmedchem.5c00442

Alexandra Sink, Eline Pottie, Samuel J. Carter, Robert J. Tombari, Verena Weber, Paolo Carloni, Giulia Rossetti, David E. Olson, Christophe P. Stove, Michael Decker

{"title":"Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq","authors":"Alexandra Sink, Eline Pottie, Samuel J. Carter, Robert J. Tombari, Verena Weber, Paolo Carloni, Giulia Rossetti, David E. Olson, Christophe P. Stove, Michael Decker","doi":"10.1021/acs.jmedchem.5c00442","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00442","url":null,"abstract":"The serotonin 2A receptor (5-HT2AR) modulates various neurotransmitter systems and is implicated in psychiatric disorders, including depression and schizophrenia. Despite progress, the detailed mechanisms of signaling at the 5-HT2AR and its therapeutic implications remain unclear, warranting further exploration. Overcoming the limitations of conventional pharmacology, photopharmacology addresses issues such as spatial selectivity and spatiotemporal resolution by incorporating light as an additional external control element. To study the roles of G protein- and β-arrestin2-dependent signaling pathways independently, we designed a photoswitchable, pathway-selective 5-HT2AR ligand. In radioligand binding studies, the cis-photoisomer has a greater affinity than the trans-isomer at the 5-HT2AR and binds at nanomolar concentrations. In two highly analogous functional assays, the photoswitchable ligand showed a preference for β-arrestin2 recruitment over mini-Gαq recruitment relative to LSD, providing a compelling tool for investigating the role of β-arrestin2 recruitment in 5-HT2AR signaling and elucidating its potential role in psychedelic effects.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 and Pharmacological Evaluation of Potent and Highly Selective PARP1 Inhibitors 强效和高选择性PARP1抑制剂的发现和药理学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-18 DOI: 10.1021/acs.jmedchem.5c00185

Tao Guo, Yongting Yuan, Ziyan Ma, Yurong Zou, Minghai Tang, Zhongning Guo, Zhiyuan Fu, Weichen Bo, Peng Wang, Shuai Liu, Hao Huang, Junfeng Hu, Zhuang Yang, Tao Jia, Taijin Wang, Lijuan Chen

{"title":"Discovery and Pharmacological Evaluation of Potent and Highly Selective PARP1 Inhibitors","authors":"Tao Guo, Yongting Yuan, Ziyan Ma, Yurong Zou, Minghai Tang, Zhongning Guo, Zhiyuan Fu, Weichen Bo, Peng Wang, Shuai Liu, Hao Huang, Junfeng Hu, Zhuang Yang, Tao Jia, Taijin Wang, Lijuan Chen","doi":"10.1021/acs.jmedchem.5c00185","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00185","url":null,"abstract":"The first-generation approved PARP inhibitors (PARPi) inhibit both PARP1 and PARP2, which may result in significant hematological toxicity. To overcome this potential issue, we designed and synthesized a series of small molecules that are highly selective PARP1 inhibitors. Among these, (S)-G9 exhibited an IC50 of 0.19 nM against PARP1, with a remarkable 137-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC50 of 1.5 nM. Furthermore, (S)-G9 is a PARP1 selective trapper, with a thousand-fold less activity toward PARP2. (S)-G9 inhibited tumor growth in the BRCA mutant MDA-MB-436 xenograft model and showed synergistic efficacy in combination with irinotecan in the HCT116 xenograft model, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer. These findings indicate that the strategy proposed in this study is highly significant for the development of selective PARP1 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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