Journal of Medicinal Chemistry最新文献_第10页

Journal of Medicinal Chemistry Collection: Drug Discovery in the UK 药物化学杂志》文集：英国的药物发现

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-17 DOI: 10.1021/acs.jmedchem.4c0205310.1021/acs.jmedchem.4c02053

Simon E. Ward*, and , Emmanuel H. Demont*,

引用次数: 0

Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors 结构引导的构象限制导致产生高亲和性、选择性和细胞活性的基于四氢异喹啉的非共价 Keap1-Nrf2 抑制剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-17 DOI: 10.1021/acs.jmedchem.4c0122110.1021/acs.jmedchem.4c01221

Yuting Qin, Cecilie Poulsen, Dilip Narayanan, Camilla B. Chan, Xiangrong Chen, Beatriz Ralsi Montes, Kim T. Tran, Elina Mukminova, Chunyu Lin, Michael Gajhede, Alex N. Bullock, David Olagnier and Anders Bach*,

{"title":"Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors","authors":"Yuting Qin, Cecilie Poulsen, Dilip Narayanan, Camilla B. Chan, Xiangrong Chen, Beatriz Ralsi Montes, Kim T. Tran, Elina Mukminova, Chunyu Lin, Michael Gajhede, Alex N. Bullock, David Olagnier and Anders Bach*, ","doi":"10.1021/acs.jmedchem.4c0122110.1021/acs.jmedchem.4c01221","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01221https://doi.org/10.1021/acs.jmedchem.4c01221","url":null,"abstract":"Inhibition of the protein–protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as an attractive approach for treating oxidative stress-related diseases. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed by a conformational restriction strategy of our fluorenone-based compounds previously identified by fragment-based drug discovery. The design was guided by X-ray cocrystal structures, and the subsequent optimization process aimed at improving affinity, cellular activity, and metabolic stability. From the noncyclic compound 7 (Ki = 2.9 μM), a new series of tetrahydroisoquinoline-based Keap1 inhibitors with up to 223-fold improvement in binding affinity (57, Ki = 13 nM), better metabolic stability, and enhanced cellular activity was obtained. In addition, the compounds showed selectivity for the Keap1 Kelch domain across a panel of 15 homologous proteins. We thereby demonstrate the utility of cyclic rigidification in the design of potent and more drug-like Keap1-Nrf2 inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"18828–18864 18828–18864"},"PeriodicalIF":6.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640689","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

“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency 高配体效率苯并噻唑类艾滋病毒噬菌体调制剂的 "伪基质包膜"/自由能扰动引导设计与机理研究

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-17 DOI: 10.1021/acs.jmedchem.4c0154410.1021/acs.jmedchem.4c01544

Shujing Xu, Shuo Wang, Yang Zhou, Nicholas Foley, Lin Sun, Laura Walsham, Kai Tang, Dazhou Shi, Xiaoyu Shi, Zhijiao Zhang, Xiangyi Jiang, Shenghua Gao, Xinyong Liu, Christophe Pannecouque*, David C. Goldstone*, Alexej Dick* and Peng Zhan*,

{"title":"“Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency","authors":"Shujing Xu, Shuo Wang, Yang Zhou, Nicholas Foley, Lin Sun, Laura Walsham, Kai Tang, Dazhou Shi, Xiaoyu Shi, Zhijiao Zhang, Xiangyi Jiang, Shenghua Gao, Xinyong Liu, Christophe Pannecouque*, David C. Goldstone*, Alexej Dick* and Peng Zhan*, ","doi":"10.1021/acs.jmedchem.4c0154410.1021/acs.jmedchem.4c01544","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01544https://doi.org/10.1021/acs.jmedchem.4c01544","url":null,"abstract":"Based on our proposed “pseudosubstrate envelope” concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, IC-1k, exhibited an EC50 of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, IC-1k emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that IC-1k targeted HIV-1 CA within the chemical space of the “pseudosubstrate envelope”. Further mechanistic studies revealed a dual-stage inhibition profile: IC-1k disrupted early-stage capsid–host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for IC-1k (T1/2 = 91.3 min) compared to PF74 (T1/2 = 0.7 min), alongside a favorable safety profile. Overall, IC-1k presents a promising lead compound for further optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19057–19076 19057–19076"},"PeriodicalIF":6.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640694","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 Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis 发现 Janus 激酶和组蛋白去乙酰化酶双重抑制剂作为治疗银屑病的新策略

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-16 DOI: 10.1021/acs.jmedchem.4c0168110.1021/acs.jmedchem.4c01681

Weijie Hu, Jing Shen, Chenchen Zhou, Zongguang Tai, Quangang Zhu, Zhongjian Chen, Yahui Huang* and Chunquan Sheng*,

{"title":"Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis","authors":"Weijie Hu, Jing Shen, Chenchen Zhou, Zongguang Tai, Quangang Zhu, Zhongjian Chen, Yahui Huang* and Chunquan Sheng*, ","doi":"10.1021/acs.jmedchem.4c0168110.1021/acs.jmedchem.4c01681","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01681https://doi.org/10.1021/acs.jmedchem.4c01681","url":null,"abstract":"Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11i significantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK inhibitor momelotinib, HDAC inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19267–19281 19267–19281"},"PeriodicalIF":6.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640597","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

68Ga-Labeled TRAP-Based Glycoside Trimers for Imaging of the Functional Liver Reserve 68Ga 标记的基于 TRAP 的糖苷三聚体用于肝脏功能储备成像

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-16 DOI: 10.1021/acs.jmedchem.4c0200610.1021/acs.jmedchem.4c02006

Maximilian A. Zierke, Christine Rangger, Kimia Samadikhah, Christoph Kreutz, Andreas M. Schmid and Roland Haubner*,

{"title":"68Ga-Labeled TRAP-Based Glycoside Trimers for Imaging of the Functional Liver Reserve","authors":"Maximilian A. Zierke, Christine Rangger, Kimia Samadikhah, Christoph Kreutz, Andreas M. Schmid and Roland Haubner*, ","doi":"10.1021/acs.jmedchem.4c0200610.1021/acs.jmedchem.4c02006","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02006https://doi.org/10.1021/acs.jmedchem.4c02006","url":null,"abstract":"The exclusive asialoglycoprotein receptor (ASGR) expression on hepatocytes makes it an attractive target for imaging of the functional liver reserve. Here, we present a set of TRAP-based glycoside trimers and evaluate their imaging properties compared to the gold standard [99mTc]Tc-GSA. The click-chemistry-based synthesis approach provided easy access to trimeric low-molecular-weight compounds. Labeling with 68Ga was carried out in high radiochemical yields (>99%). Complexes showed high stability and hydrophilicity. Protein binding ranged between 10 and 25%. Highest binding affinity (IC50) and best liver accumulation were found for [68Ga]Ga-T3N3, followed by [68Ga]Ga-T3G3 and [68Ga]Ga-T0G3. Rapid elimination from the rest of the body resulted in excellent target-to-background ratios. Our studies confirmed that high ASGR uptake depends on the correct spacer design and that N-acetylgalactosamine improves targeting properties in vivo. Thus, [68Ga]Ga-T3N3 represents a new low-molecular-weight radiopharmaceutical with pharmacokinetics similar to those of [99mTc]Tc-GSA.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19668–19677 19668–19677"},"PeriodicalIF":6.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c02006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Propionic Acid Derivatives with a 5-THIQ Core as Potent and Orally Bioavailable Keap1–Nrf2 Protein–Protein Interaction Inhibitors for Acute Kidney Injury 发现以 5-THIQ 为核心的丙酸衍生物，作为强效口服生物活性 Keap1-Nrf2 蛋白-蛋白相互作用抑制剂治疗急性肾损伤

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-10 DOI: 10.1021/acs.jmedchem.4c0168710.1021/acs.jmedchem.4c01687

Zeyu Shi, Yong Zhang, Xinyu Wang, Jingshu Tang, Yuying Kang, Jiahuan Hu, Li Li, Beibei Yang, Si Chen, Qiong Xiao*, Jiaqi Lan*, Jinping Hu*, Ying Peng* and Dali Yin,

{"title":"Discovery of Propionic Acid Derivatives with a 5-THIQ Core as Potent and Orally Bioavailable Keap1–Nrf2 Protein–Protein Interaction Inhibitors for Acute Kidney Injury","authors":"Zeyu Shi, Yong Zhang, Xinyu Wang, Jingshu Tang, Yuying Kang, Jiahuan Hu, Li Li, Beibei Yang, Si Chen, Qiong Xiao*, Jiaqi Lan*, Jinping Hu*, Ying Peng* and Dali Yin, ","doi":"10.1021/acs.jmedchem.4c0168710.1021/acs.jmedchem.4c01687","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01687https://doi.org/10.1021/acs.jmedchem.4c01687","url":null,"abstract":"Keap1 plays a crucial role in regulating the Nrf2-mediated cytoprotective response and is increasingly targeted for oxidative stress-related diseases. Using small molecules to disrupt the Keap1–Nrf2 protein–protein interaction (PPI) has emerged as a new strategy for developing Nrf2 activators. Through extensive structure–activity relationship studies, we identified compound 56, which features a unique 5-tetrahydroisoquinoline scaffold and acts as a potent inhibitor of the Keap1–Nrf2 PPI. Compound 56 exhibited significant inhibitory activity (IC50 = 16.0 nM) and tight Keap1 binding affinity (Kd = 3.07 nM), along with acceptable oral bioavailability (F = 20%). Notably, 56 enhanced antioxidant defenses in HK-2 renal tubular epithelial cells and significantly reduced plasma creatinine and blood urea nitrogen levels in acute kidney injury (AKI) mice. These findings collectively position compound 56 as a promising candidate for the treatment of AKI.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19247–19266 19247–19266"},"PeriodicalIF":6.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641057","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

Phosphorylation as an Effective Tool to Improve Stability and Reduce Toxicity of Antimicrobial Peptides 磷酸化是提高抗菌肽稳定性和降低其毒性的有效工具

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-09 DOI: 10.1021/acs.jmedchem.4c0117910.1021/acs.jmedchem.4c01179

Zufang Ba, Yu Wang, Yinyin Yang, Bingqian Ren, Beibei Li, Xu Ouyang, Jingying Zhang, Tingting Yang, Yao Liu, Yuhuan Zhao, Ping Yang, Xiaoyan Wu, Wenbo Mao, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou* and Jingman Ni*,

{"title":"Phosphorylation as an Effective Tool to Improve Stability and Reduce Toxicity of Antimicrobial Peptides","authors":"Zufang Ba, Yu Wang, Yinyin Yang, Bingqian Ren, Beibei Li, Xu Ouyang, Jingying Zhang, Tingting Yang, Yao Liu, Yuhuan Zhao, Ping Yang, Xiaoyan Wu, Wenbo Mao, Chao Zhong, Hui Liu, Yun Zhang, Sanhu Gou* and Jingman Ni*, ","doi":"10.1021/acs.jmedchem.4c0117910.1021/acs.jmedchem.4c01179","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01179https://doi.org/10.1021/acs.jmedchem.4c01179","url":null,"abstract":"Developing a straightforward and effective strategy to modify antimicrobial peptides (AMPs) is crucial in overcoming the challenges posed by their instability and toxicity. Phosphorylation can reduce toxicity and improve the stability of AMPs. Based on these, we designed a series of peptides and their corresponding phosphorylated forms. The results showed that all phosphorylated peptides displayed reduced toxicity and enhanced stability compared to their unphosphorylated counterparts. Among them, W3BipY8-P stood out as the most promising peptide, exhibiting similar antibacterial activity as its unphosphorylated analog W3BipY8 but with significantly reduced hemolytic activity (19-fold decrease), cytotoxicity (3.3-fold decrease), and an extended serum half-life 6.3 times longer than W3BipY8. W3BipY8-P exerted bactericidal effects by disrupting bacterial membranes. Notably, W3BipY8-P significantly prolonged the survival of bacteria-infected animals while its LD50 was 4.2 times higher than that of W3BipY8. These findings highlight phosphorylation as an effective strategy for improving the antimicrobial properties of AMPs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"18807–18827 18807–18827"},"PeriodicalIF":6.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641029","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

RAB32 mutation in Parkinson's disease. 帕金森病中的 RAB32 基因突变。

IF 46.5 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-01 DOI: 10.1016/S1474-4422(24)00325-9

Pilar Gómez-Garre, Miguel Martín-Bórnez, Pablo Mir

引用次数: 0

Differential diagnosis of suspected multiple sclerosis: considerations in people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia. 疑似多发性硬化症的鉴别诊断：北美、北欧和澳大拉西亚少数民族和种族背景人群的考虑因素。

IF 46.5 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-01 DOI: 10.1016/S1474-4422(24)00288-6

Lilyana Amezcua, Dalia Rotstein, Afsaneh Shirani, Olga Ciccarelli, Daniel Ontaneda, Melinda Magyari, Victor Rivera, Dorlan Kimbrough, Ruth Dobson, Bruce Taylor, Mitzi Williams, Ruth Ann Marrie, Brenda Banwell, Bernhard Hemmer, Scott D Newsome, Jeffrey A Cohen, Andrew J Solomon, Walter Royal

{"title":"Differential diagnosis of suspected multiple sclerosis: considerations in people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia.","authors":"Lilyana Amezcua, Dalia Rotstein, Afsaneh Shirani, Olga Ciccarelli, Daniel Ontaneda, Melinda Magyari, Victor Rivera, Dorlan Kimbrough, Ruth Dobson, Bruce Taylor, Mitzi Williams, Ruth Ann Marrie, Brenda Banwell, Bernhard Hemmer, Scott D Newsome, Jeffrey A Cohen, Andrew J Solomon, Walter Royal","doi":"10.1016/S1474-4422(24)00288-6","DOIUrl":"10.1016/S1474-4422(24)00288-6","url":null,"abstract":"The differential diagnosis of suspected multiple sclerosis has been developed using data from North America, northern Europe, and Australasia, with a focus on White populations. People from minority ethnic and racial backgrounds in regions where prevalence of multiple sclerosis is high are more often negatively affected by social determinants of health, compared with White people in these regions. A better understanding of changing demographics, the clinical characteristics of people from minority ethnic or racial backgrounds, and the social challenges they face might facilitate equitable clinical approaches when considering a diagnosis of multiple sclerosis. Neuromyelitis optica, systemic lupus erythematous, neurosarcoidosis, infections, and cerebrovascular conditions (eg, hypertension) should be considered in the differential diagnosis of multiple sclerosis for people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia. The diagnosis of multiple sclerosis in people from a minority ethnic or racial background in these regions requires a comprehensive approach that considers the complex interplay of immigration, diagnostic inequity, and social determinants of health.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"23 10","pages":"1050-1062"},"PeriodicalIF":46.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290353","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

RAB32 mutation in Parkinson's disease. 帕金森病中的 RAB32 基因突变。

IF 46.5 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-01 DOI: 10.1016/S1474-4422(24)00327-2

Yuwen Zhao, Hongxu Pan, Jifeng Guo, Beisha Tang, Zhenhua Liu

引用次数: 0