Journal of Medicinal Chemistry最新文献_第7页

Drug and Clinical Candidate Drug Data in ChEMBL ChEMBL中的药物和临床候选药物数据

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-19 DOI: 10.1021/acs.jmedchem.5c00920

Fiona M. I. Hunter, Harris Ioannidis, A. Patrícia Bento, Nicolas Bosc, Sybilla Corbett, Eloy Felix, M. Paula Magarinos, Emma Manners, Ines A. Smit, Marleen de Veij, Noel M. O’Boyle, Barbara Zdrazil, Andrew R. Leach

引用次数: 0

Large Library Docking and Biophysical Analysis of Small-Molecule TMPRSS2 Inhibitors 小分子TMPRSS2抑制剂的大文库对接及生物物理分析

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-19 DOI: 10.1021/acs.jmedchem.4c03089

Bryan J. Fraser, Nicholas J. Young, Brian J. Bender, Stefan Gahbauer, Olzhas Ilyassov, Ryan P. Wilson, Yanjun Li, Almagul Seitova, André Luiz Lourenço, Dong Hee Chung, Conner Bardine, François Bénard, Brian K. Shoichet, Charles S. Craik, Cheryl H. Arrowsmith

{"title":"Large Library Docking and Biophysical Analysis of Small-Molecule TMPRSS2 Inhibitors","authors":"Bryan J. Fraser, Nicholas J. Young, Brian J. Bender, Stefan Gahbauer, Olzhas Ilyassov, Ryan P. Wilson, Yanjun Li, Almagul Seitova, André Luiz Lourenço, Dong Hee Chung, Conner Bardine, François Bénard, Brian K. Shoichet, Charles S. Craik, Cheryl H. Arrowsmith","doi":"10.1021/acs.jmedchem.4c03089","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03089","url":null,"abstract":"Transmembrane protease serine-2 (TMPRSS2) is an essential host entry factor in human airways for SARS-CoV-2 and influenza A/B and has presented as a target for antiviral drug development; however, no clinically viable oral small-molecule TMPRSS2 inhibitors have been developed to date. Here, we perform two large-scale docking campaigns to identify covalent and noncovalent TMPRSS2 small-molecule inhibitors using a homology model and crystal structure. We establish a pipeline to rapidly screen TMPRSS2 inhibitors and then interrogate the potency, selectivity, and biophysical properties of covalent and noncovalent inhibition using enzyme kinetics on synthetic peptide and protein substrates and differential scanning fluorimetry. Furthermore, we established a readily crystallizable form of TMPRSS2 protein that produced high-resolution crystal structures with nafamostat, ‘157, and 6-amidino-2-naphthol. A novel noncovalent inhibitor scaffold is biochemically validated as a potential avenue for developing TMPRSS2-selective inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089643","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

Therapeutic Potential of Novel Antimicrobial Peptide Pap12-6-10: Mechanisms of Antibacterial and Anti-inflammatory Action Against Gram-Negative Sepsis. 新型抗菌肽Pap12-6-10的治疗潜力：抗革兰氏阴性脓毒症的抗菌和抗炎作用机制

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-19 DOI: 10.1021/acs.jmedchem.5c01360

Byeongkwon Kim,Jin Kyeong Lee,Minwon Son,Hyeju Lee,Chae Yeong Lee,Junho Jeong,Dasom Song,Heewoong Yoon,Eunha Hwang,Myeong Seon Jeong,Jiwon Seo,Yangmee Kim

{"title":"Therapeutic Potential of Novel Antimicrobial Peptide Pap12-6-10: Mechanisms of Antibacterial and Anti-inflammatory Action Against Gram-Negative Sepsis.","authors":"Byeongkwon Kim,Jin Kyeong Lee,Minwon Son,Hyeju Lee,Chae Yeong Lee,Junho Jeong,Dasom Song,Heewoong Yoon,Eunha Hwang,Myeong Seon Jeong,Jiwon Seo,Yangmee Kim","doi":"10.1021/acs.jmedchem.5c01360","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01360","url":null,"abstract":"To develop novel antibiotics, we engineered 12-mer peptides derived from the N-terminus of papiliocin. Pap12-6-10 emerged as a potent antibacterial agent against multidrug-resistant Gram-negative bacteria, demonstrating a low propensity for resistance development. Pap12-6-10 exerts its antibacterial activity by permeabilizing bacterial membranes through binding to lipopolysaccharide (LPS), inducing oxidative stress that leads to cell death. Pap12-6-10 modulates LPS-induced inflammatory responses by selectively targeting the TLR4 signaling pathways. Structural analysis using NMR, surface plasmon resonance, docking, and molecular dynamics simulations suggested that Pap12-6-10 binds to the hydrophobic pocket of MD-2, thereby preventing the LPS-induced dimerization of the TLR4/MD-2 complex, which is essential for inflammatory signaling during sepsis. In the Escherichia coli K1 and carbapenem-resistant Acinetobacter baumannii-induced sepsis mouse model Pap12-6-10 protected organ damage from septic shock and displayed significant therapeutic effects while maintaining low cytotoxicity. This study highlights its potential as a valuable candidate for treating Gram-negative infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083375","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

Design, Synthesis, and Evaluation of Antifibrotic Activity of Nonsteroidal VDR Agonists Featuring 1,6-Naphthol as a CD-Ring Surrogate. 以1,6-萘酚为cd环替代物的非甾体VDR激动剂抗纤维化活性的设计、合成和评价。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-19 DOI: 10.1021/acs.jmedchem.5c01753

Yi Gao,Yue Wu,Chun Guan,Nuo Cheng,Yu Tong,Cong Wang,Can Zhang

{"title":"Design, Synthesis, and Evaluation of Antifibrotic Activity of Nonsteroidal VDR Agonists Featuring 1,6-Naphthol as a CD-Ring Surrogate.","authors":"Yi Gao,Yue Wu,Chun Guan,Nuo Cheng,Yu Tong,Cong Wang,Can Zhang","doi":"10.1021/acs.jmedchem.5c01753","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01753","url":null,"abstract":"Chronic liver diseases activate hepatic stellate cells (HSCs), driving excessive deposition of extracellular matrix (ECM) and leading to liver fibrosis. Despite being a crucial precursor to cirrhosis, effective targeted antifibrotic therapies are lacking. Activation of the vitamin D receptor (VDR) has been shown to effectively alleviate liver fibrosis, yet prolonged use of currently available steroidal VDR agonists can lead to hypercalcemia. To address this issue, we performed structural optimization targeting the CD-ring and conjugated triene moiety, while preserving the A-ring and side chains, yielding 52 novel nonsteroidal VDR modulators. Among them, compounds A17, B15, and B20 demonstrated favorable VDR binding affinity and potent antifibrotic activity in vitro. Notably, compound B15 significantly reduced fibrosis without inducing hypercalcemia in a murine model of carbon tetrachloride (CCl4)-induced liver fibrosis. These findings highlight the potential of these nonsteroidal VDR modulators and warrant further investigation as promising therapeutics for liver fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083377","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

Light-Driven ESIPT-Based Anthraquinone Analogues for Synergistic Fluorescent Self-Reporting and Photodynamic Therapy of Malignant Tumors. 基于esipt的蒽醌类似物协同荧光自我报告和光动力治疗恶性肿瘤。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-19 DOI: 10.1021/acs.jmedchem.5c02158

Jiaona Han,Meng Yang,Yao He,Kui Wang,Lingyue Zhang,Rui Zhang,Hui Qiao,Yonggang Yang,Hua Zhang

{"title":"Light-Driven ESIPT-Based Anthraquinone Analogues for Synergistic Fluorescent Self-Reporting and Photodynamic Therapy of Malignant Tumors.","authors":"Jiaona Han,Meng Yang,Yao He,Kui Wang,Lingyue Zhang,Rui Zhang,Hui Qiao,Yonggang Yang,Hua Zhang","doi":"10.1021/acs.jmedchem.5c02158","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02158","url":null,"abstract":"The intelligent integration of intervention and self-reporting signals from photosensitizers (PSs) in living organisms remains a challenge. Herein, we developed two anthraquinone-based PSs (1H-D1 and 1H8H-D1) through polymerization and end-group modification approaches, which exhibited weak fluorescence due to disruption of the excited-state intramolecular proton transfer (ESIPT) process. These dimer PSs exhibited mitochondrial targeting and released monomer natural products─anthraquinone derivatives (1H and 1H8H) under light irradiation. The released monomers restored ESIPT fluorescence and effectively generated O2•- via the type-I reaction under continuous light irradiation, thereby suppressing the growth of tumor cells. Notably, in vivo experiments showed that 1H-D1 significantly inhibited tumor growth (Vlight/Vcontrol ≈ 0.24). At the same time, the fluorescence intensity of 1H-D1 was greatly enhanced, providing excellent guidance on the treatment outcome. It can be seen that this dual-effect synergy strategy offers a promising approach for designing natural product-based self-reporting PSs with enhanced therapeutic and diagnostic capabilities.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083376","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

Development of Potent and Selective Dual PPARδ/sEH Modulators from an AI-Designed Scaffold. 从人工智能设计支架中开发有效和选择性的双PPARδ/sEH调节剂。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI: 10.1021/acs.jmedchem.5c01915

Xiu Ge,Till Kasch,Max Lewandowski,Lilia Weizel,Julian A Marschner,Jörg Pabel,Ewgenij Proschak,Daniel Merk

{"title":"Development of Potent and Selective Dual PPARδ/sEH Modulators from an AI-Designed Scaffold.","authors":"Xiu Ge,Till Kasch,Max Lewandowski,Lilia Weizel,Julian A Marschner,Jörg Pabel,Ewgenij Proschak,Daniel Merk","doi":"10.1021/acs.jmedchem.5c01915","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01915","url":null,"abstract":"Designed polypharmacology is an evolving concept to achieve improved therapeutic efficacy in multifactorial diseases. Dual soluble epoxide hydrolase (sEH) inhibition and peroxisome proliferator-activated receptor δ (PPARδ) activation hold promise as designed polypharmacology in metabolic dysfunction and associated liver diseases by improving whole-body energy balance, decreasing hepatic inflammation and lipotoxicity, and providing cardiovascular protection. Here we developed dual PPARδ/sEH modulators from a computationally designed lead fusing pharmacophore elements of ligands for both targets. Systematic SAR exploration of the scaffold identified substructures driving PPARδ agonism or sEH inhibition and a combination of favored modifications provided potent dual modulators. The optimized dual ligands displayed balanced activity on both proteins of interest and selectivity over related targets including the PPARα/γ subtypes. Additionally, we identified structurally matched selective modulators of both targets of interest as controls, forming a set of tools to explore the therapeutic potential of PPARδ/sEH-targeted polypharmacology.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083409","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

Synthesis and Biological Evaluation of Nipecotic Acid Derivatives with Terminally Double-Substituted Allenic Spacers as mGAT4 Inhibitors 以末端双取代的异位间隔剂作为mGAT4抑制剂的Nipecotic酸衍生物的合成及生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI: 10.1021/acs.jmedchem.5c00520

Maren Jung, Kinga Sałat, Georg Höfner, Jörg Pabel, Elżbieta Wyska, Marek Sierżęga, Anna Furgała-Wojas, Christoph G. W. Gertzen, Holger Gohlke, Klaus T. Wanner

{"title":"Synthesis and Biological Evaluation of Nipecotic Acid Derivatives with Terminally Double-Substituted Allenic Spacers as mGAT4 Inhibitors","authors":"Maren Jung, Kinga Sałat, Georg Höfner, Jörg Pabel, Elżbieta Wyska, Marek Sierżęga, Anna Furgała-Wojas, Christoph G. W. Gertzen, Holger Gohlke, Klaus T. Wanner","doi":"10.1021/acs.jmedchem.5c00520","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00520","url":null,"abstract":"Within a series of nipecotic acid derivatives with a four- and five-carbon atom allenic spacer, respectively, connecting the nitrogen of nipecotic acid with up to two aromatic residues, a highly potent mGAT4 inhibitor has been identified. Its (S)-enantiomer, (S)-1-[4,4-bis(4-chlorophenyl)buta-2,3-dien-1-yl]piperidine-3-carboxylic acid [(S)-8d, DDPM-3960], displays potencies in the higher nanomolar range at mGAT4 (pIC50 = 6.59 ± 0.01) and its human equivalent hGAT-3 (pIC50 = 6.49 ± 0.10). It is thus significantly more potent than the well-known mGAT4 inhibitor (S)-SNAP-5114. Molecular docking rationalizes the enantioselectivity of the inhibitory potency. DDPM-3960 is highly bound to serum proteins (>99%), has good brain penetration and stability. It revealed significant anticonvulsant activity in several mouse models of chemically- and electrically induced seizures. Additionally, anxiolytic-like properties of DDPM-3960 were found. These beneficial biological effects observed in mice were accompanied by sedation but not motor impairments, making DDPM-3960 an interesting lead structure for further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084222","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

Phototoxicity of Half-Sandwich Rhodium(III) Complexes with Anthracene and Biphenyl Substituents toward Mammalian Cancer Cells and Multicellular Tumor Spheroids 含蒽和联苯取代基的半夹层铑（III）配合物对哺乳动物癌细胞和多细胞肿瘤球体的光毒性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI: 10.1021/acs.jmedchem.5c01406

Petra Andršová, Jitka Prachařová, Vojtěch Novohradský, Slavomíra Šterbinská, Pavel Štarha, Jana Kašpárková, Viktor Brabec

{"title":"Phototoxicity of Half-Sandwich Rhodium(III) Complexes with Anthracene and Biphenyl Substituents toward Mammalian Cancer Cells and Multicellular Tumor Spheroids","authors":"Petra Andršová, Jitka Prachařová, Vojtěch Novohradský, Slavomíra Šterbinská, Pavel Štarha, Jana Kašpárková, Viktor Brabec","doi":"10.1021/acs.jmedchem.5c01406","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01406","url":null,"abstract":"We report the synthesis and characterization of three half-sandwich rhodium(III) complexes incorporating anthracene and biphenyl moieties to investigate their photobiological activity. Complexes 1 and 2, bearing anthracene-based Schiff base ligand, displayed pronounced phototoxicity upon blue-light irradiation, with complex 2 achieving a phototoxicity index of 144 in A375 melanoma cells. In contrast, complex 3, lacking the anthracene unit, was photoinactive. Photoactivation of complexes 1 and 2 induced −N═CH– Schiff bond cleavage, releasing anthracene-9-carbaldehyde, as confirmed by UV–vis and mass spectrometry. Blue light also enabled catalytic oxidation of NADH to NAD+. Mechanistic studies revealed oncosis-like cell death mediated by reactive oxygen species. Both complexes retained activity in 3D tumor spheroids, demonstrating efficient tissue penetration. These results identify anthracene-functionalized rhodium(III) complexes as promising candidates for photodynamic therapy and provide, to our knowledge, the first detailed mechanistic insight into photopotentiation in half-sandwich rhodium systems.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077931","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

De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy 一种具有抗肾纤维化疗效的白介素-11大环肽拮抗剂的新发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI: 10.1021/acs.jmedchem.5c01432

ChunMei An, Wenfeng Cai, Peiying Li, Jian Li, Na Zhao, Xu Yang, Keqiang Li, Ningning Pang, Xing Cheng, Naiyuan Wang, Dong Guo, Yizhen Yin, Xiaochun Xiong

{"title":"De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy","authors":"ChunMei An, Wenfeng Cai, Peiying Li, Jian Li, Na Zhao, Xu Yang, Keqiang Li, Ningning Pang, Xing Cheng, Naiyuan Wang, Dong Guo, Yizhen Yin, Xiaochun Xiong","doi":"10.1021/acs.jmedchem.5c01432","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01432","url":null,"abstract":"Emerging evidence has highlighted the pathological involvement of interleukin-11 (IL-11) in fibrotic disorders. In this study, we identified a novel peptide antagonist 4L2 through the random nonstandard peptide integrated discovery (RaPID) system, which exhibits a high binding toward IL-11, with a KD value of 5.26 nM. Additionally, cell-based assays revealed that 4L2 displays a moderate antagonistic activity, with an IC50 value of 22.7 ± 1.9 μM. Through performing alanine scanning and subsequent structural optimization, we developed an improved variant, 4L2-P13D, which showed significantly enhanced antagonistic activity, with an IC50 value of 2.8 ± 0.5 μM. Furthermore, 4L2-P13D demonstrated the significant renoprotective effects in in vitro and in vivo models. These findings indicate that the analogue 4L2-P13D represents a promising lead candidate for developing targeted IL-11 therapeutics against renal fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"89 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077870","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

Comparative Profiling and Chemogenomics Application of Chemical Tools for NR4A Nuclear Receptors. NR4A核受体化学工具的比较谱分析及化学基因组学应用

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI: 10.1021/acs.jmedchem.5c00459

Sabine Willems,Vasily Morozov,Julian A Marschner,Daniel Merk

引用次数: 0