Journal of Medicinal Chemistry最新文献

{"title":"Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors","authors":"Florian Wittlinger,&nbsp;Surbhi P. Chitnis,&nbsp;Calvin D. Pham,&nbsp;Tahereh Damghani,&nbsp;Kishan B. Patel,&nbsp;Mareike Möllers,&nbsp;Ilse K. Schaeffner,&nbsp;Omobolanle A. Abidakun,&nbsp;Matthew Q. Deng,&nbsp;Blessing C. Ogboo,&nbsp;Alexander Rasch,&nbsp;Tyler S. Beyett,&nbsp;Brian Buckley,&nbsp;Frederic Feru,&nbsp;Tatiana Shaurova,&nbsp;Cornelius Knappe,&nbsp;Michael J. Eck,&nbsp;Pamela A. Hershberger,&nbsp;David A. Scott,&nbsp;Asher L. Brandt,&nbsp;Stefan A. Laufer* and David E. Heppner*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0231110.1021/acs.jmedchem.4c02311","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02311https://doi.org/10.1021/acs.jmedchem.4c02311","url":null,"abstract":"<p >Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure–activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I¹/₂ inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as “Type V” bivalent inhibitors.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21438–21469 21438–21469"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849960","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}

{"title":"Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains","authors":"Oren L. Lederberg,&nbsp;Nicholas L. Yan,&nbsp;Julian Sanchez,&nbsp;Wen Ren,&nbsp;Carl Ash,&nbsp;Steven J. Wilkens,&nbsp;Huang Qiu,&nbsp;Bo Qin,&nbsp;Virginia H. Grant,&nbsp;Alex B. Jackman,&nbsp;Robyn L. Stanfield*,&nbsp;Ian A. Wilson*,&nbsp;H. Michael Petrassi*,&nbsp;Derek Rhoades* and Jeffery W. Kelly*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0177310.1021/acs.jmedchem.4c01773","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01773https://doi.org/10.1021/acs.jmedchem.4c01773","url":null,"abstract":"<p >Kinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior λ full-length LC dimer (FL LC₂) kinetic stabilizers exhibited considerable plasma protein binding. We hypothesized that the coumarin “aromatic core” of the stabilizers was responsible for the undesirable plasma protein binding. Here, we describe structure–activity relationship (SAR) data initially focused on replacing the coumarin aromatic core. 2-pyridones proved suitable replacements. We subsequently optimized the “anchor substructure” in the context of 2-pyridones, resulting in potent λ FL LC₂ kinetic stabilizers exhibiting reduced plasma protein binding. The 3-methyl- or 3-ethyl-3-phenylpyrrolidine–2-pyridone scaffold stabilized multiple AL patient-derived λ FL LC₂s in human plasma. This, coupled with X-ray crystallographic data, indicates that 3-alkyl-3-phenylpyrrolidine–2-pyridone-based stabilizers are promising candidates for treating the proteinopathy component of AL.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21070–21105 21070–21105"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849961","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}

{"title":"What Is Pink Cocaine? The Dark Reality behind a Colorful Name","authors":"Lisa Barbaro, Jacob L. Bouchard","doi":"10.1021/acs.jmedchem.4c02821","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02821","url":null,"abstract":"In recent months, a synthetic drug commonly referred to as “pink cocaine” has captured headlines, with notable public figures reportedly linked to its hidden dangers. (1,2) Public fascination with what appears to be a new and mysterious “designer” drug has spurred a slew of media attention. The reality is that pink cocaine is neither a new drug nor cocaine; rather, it’s an inconsistent and unpredictable formulation of existing drugs and adulterants─primarily ketamine and MDMA─branded with a distinctive rosy hue. This deceptive tactic, designed to lure and entice a new wave of recreational drug users, has little regard for the serious health risks posed by the complex and dangerous interactions among its components. Pink cocaine is an older phenomenon than the recent headlines suggest. It has been circulating in Colombia, where it is more commonly known as “tusi” or “tusibi”, since the late 2000s, with the earliest reports dating back to 2012. (3) The nicknames “tusibi” and the shortened “tusi” derive from a phonetic translation of “2C-B”, a hallucinogenic phenethylamine first synthesized by Alexander Shulgin in 1974. (4) Known to induce euphoria and hallucinations reportedly similar to a blend of MDMA and LSD, 2C-B belongs to the broader “2C-X family” of drugs (psychedelic phenethylamines containing 2,5-dimethoxy substitution) and was widely popular in the European rave and party scenes in the 1990s. In the late 2000s, 2C-B surfaced in Colombia’s vibrant nightlife, where its reputation as a “designer” drug began to solidify. The signature pink hue was introduced as a way to mask the unpleasant and harsh taste of 2C-B when consumed, the food coloring and aromatic additives transforming the drug into a visually enticing and instantly recognizable powder. The drug’s evolution to the pink cocaine product of today was driven by the surge in demand for 2C-B in the Colombian market. As supply chains struggled to keep up, dealers began cutting 2C-B with more accessible and cheaper psychoactive substances to mimic its stimulant and hallucinogenic effects. (5) Eventually, 2C-B disappeared from the formulation altogether, giving way to the current iterations of pink cocaine. Recently, law enforcement agencies and drug-checking services have reported an uptick in pink cocaine’s presence beyond Latin America, particularly in Europe and North America. (6,7) In the United States, pink cocaine has slowly gained popularity within the club scenes in New York, Miami, and Los Angeles. In 2023, multiple large-scale seizures in the U.S. further underscored its growing popularity. The primary danger of pink cocaine lies in the unknown. Not only is the name itself misleading, giving the illusion of a stimulant akin to cocaine, but the user is completely unaware of the cocktail of substances hidden beneath its appealing pink shade. Aside from the pink food coloring, little about this drug is consistent. Each batch varies widely in composition and potency, exposing users ","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759966","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}

{"title":"Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains","authors":"Oren L. Lederberg, Nicholas L. Yan, Julian Sanchez, Wen Ren, Carl Ash, Steven J. Wilkens, Huang Qiu, Bo Qin, Virginia H. Grant, Alex B. Jackman, Robyn L. Stanfield, Ian A. Wilson, H. Michael Petrassi, Derek Rhoades, Jeffery W. Kelly","doi":"10.1021/acs.jmedchem.4c01773","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01773","url":null,"abstract":"Kinetic stabilization of amyloidogenic immunoglobulin light chains (LCs) through small molecule binding may become the first treatment for the proteinopathy component of light chain amyloidosis (AL). Kinetic stabilizers selectively bind to the native state over the misfolding transition state, slowing denaturation. Prior λ full-length LC dimer (FL LC₂) kinetic stabilizers exhibited considerable plasma protein binding. We hypothesized that the coumarin “aromatic core” of the stabilizers was responsible for the undesirable plasma protein binding. Here, we describe structure–activity relationship (SAR) data initially focused on replacing the coumarin aromatic core. 2-pyridones proved suitable replacements. We subsequently optimized the “anchor substructure” in the context of 2-pyridones, resulting in potent λ FL LC₂ kinetic stabilizers exhibiting reduced plasma protein binding. The 3-methyl- or 3-ethyl-3-phenylpyrrolidine–2-pyridone scaffold stabilized multiple AL patient-derived λ FL LC₂s in human plasma. This, coupled with X-ray crystallographic data, indicates that 3-alkyl-3-phenylpyrrolidine–2-pyridone-based stabilizers are promising candidates for treating the proteinopathy component of AL.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763751","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}

{"title":"Synthesis and Evaluation of 99mTc-Labeled l-Aspartic Acid as a EuK Polymer Linker for Targeting PSMA to a Novel SPECT Tumor Tracer","authors":"Zuojie Li,&nbsp;Xiaojiang Duan,&nbsp;Peiwen Han,&nbsp;Guangxing Yin,&nbsp;Yuhao Jiang,&nbsp;Qing Ruan and Junbo Zhang*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0265610.1021/acs.jmedchem.4c02656","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02656https://doi.org/10.1021/acs.jmedchem.4c02656","url":null,"abstract":"<p >The development of novel tracers targeting prostate-specific membrane antigen (PSMA) has great potential for improving the diagnosis and treatment of prostate cancer (PCa). This study aimed to improve the absolute tumor uptake and tumor-to-background ratios (TBRs) of this novel PSMA tracer by increasing the number of pharmacophores, Glu-urea-Lys (EuK), that specifically bind to PSMA. We successfully synthesized four radioligands and prepared a total of 12 stable radiotracers by coordinating ^99mTc with various coligands. [^99mTc]Tc-EUKD-EDDA showed the best pharmacokinetic properties both <i>in vitro</i> and <i>in vivo</i>. It effectively increased the absolute uptake in tumors and resulted in good tumor retention. Rapid clearance in nontarget organs resulted in high TBRs. High-contrast SPECT/CT images were obtained within 2–6 h after injection, suggesting that [^99mTc]Tc-EUKD-EDDA has great application potential in time-lapse imaging of PCa, which is important for improving the diagnostic accuracy of PCa in clinical practice.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21617–21628 21617–21628"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842560","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}

{"title":"What Is Pink Cocaine? The Dark Reality behind a Colorful Name","authors":"Lisa Barbaro*,&nbsp; and ,&nbsp;Jacob L. Bouchard,&nbsp;","doi":"10.1021/acs.jmedchem.4c0282110.1021/acs.jmedchem.4c02821","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02821https://doi.org/10.1021/acs.jmedchem.4c02821","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20733–20736 20733–20736"},"PeriodicalIF":6.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842566","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}

{"title":"Development of Novel Silicon-Based Hydrophobic Tags (SiHyT) for Targeted Proteins Degradation","authors":"Lan Ma, Kun Zhang, Ziqi Huang, Yuda Guo, Ning Liu, Jia Chen, Xinyue Wang, Ying Liu, Mei Li, Jinxiao Li, Cheng Yang, Shuangwei Liu, Guang Yang","doi":"10.1021/acs.jmedchem.4c02273","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02273","url":null,"abstract":"Recent advances in targeted protein degradation (TPD) have propelled it to the forefront of small molecular drug discovery. Among these, hydrophobic tagging (HyT) strategies have garnered significant interest. Carbon-based hydrophobic tags have been recognized as effective Hyts for degrading a variety of target proteins. In this study, we introduce a novel class of potential EGFR degraders for the first time, which combine Gefitinib with silicon-based hydrophobic tags (SiHyT). The most promising candidate, degrader <b>7</b>, which links Gefitinib to a simple TBDPS silyl ether, has shown efficacy in degrading mutant EGFRs via the ubiquitin-proteosome system (UPS) both in vitro and in vivo. Notably, degrader <b>7</b> exhibits enhanced oral bioavailability owing to its superior metabolic stability compared to traditional carbon-based Hyts. Mechanistically, it was revealed that degrader <b>7</b> disrupts EGFR stability by dissociating the EGFR-HSP90 complex and recruiting E3 ligase, RNF149. More importantly, the potent and selective PD-L1 and BTK degraders were discovered successfully by utilizing the SiHyT strategy. The development of these innovative SiHyT compounds could broaden the repertoire of HyTs, enhancing the future design of TPD agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758482","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}

{"title":"MPCD: A Multitask Graph Transformer for Molecular Property Prediction by Integrating Common and Domain Knowledge","authors":"Xixi Yang,&nbsp;Yanjing Duan,&nbsp;Zhixiang Cheng,&nbsp;Kun Li,&nbsp;Yuansheng Liu*,&nbsp;Xiangxiang Zeng and Dongsheng Cao*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0219310.1021/acs.jmedchem.4c02193","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02193https://doi.org/10.1021/acs.jmedchem.4c02193","url":null,"abstract":"<p >Molecular property prediction with deep learning often employs self-supervised learning techniques to learn common knowledge through masked atom prediction. However, the common knowledge gained by masked atom prediction dramatically differs from the graph-level optimization objective of downstream tasks, which results in suboptimal problems. Particularly for properties with limited data, the failure to consider domain knowledge results in a direct search in an immense common space, rendering it infeasible to identify the global optimum. To address this, we propose MPCD, which enhances pretraining transferability by aligning the optimization objectives between pretraining and fine-tuning with domain knowledge. MPCD also leverages multitask learning to improve data utilization and model robustness. Technically, MPCD employs a relation-aware self-attention mechanism to capture molecules’ local and global structures comprehensively. Extensive validation demonstrates that MPCD outperforms state-of-the-art methods for absorption, distribution, metabolism, excretion, and toxicity (ADMET) and physicochemical prediction across various data sizes.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21303–21316 21303–21316"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849949","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}

{"title":"Novel Benzimidazole Derivatives as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase 1 for the Potential Treatment of Inflammation, Pain, and Fever","authors":"Azize Gizem Ergül, Paul M. Jordan, Philipp Dahlke, Nur Banu Bal, Abdurrahman Olğaç, Orhan Uludağ, Oliver Werz, Burcu Çalışkan, Erden Banoglu","doi":"10.1021/acs.jmedchem.4c01883","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01883","url":null,"abstract":"Microsomal prostaglandin E₂ synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC₅₀ values of 0.27–7.0 nM in a cell-free assay for prostaglandin (PG)E₂ production. Compound <b>44</b> (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC₅₀ = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE₂ production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, <i>in vivo</i> studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760265","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}

{"title":"4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses","authors":"Atefeh Garzan,&nbsp;S. Kaleem Ahmed,&nbsp;Nicole N. Haese,&nbsp;Gauthami Sulgey,&nbsp;Samuel Medica,&nbsp;Jessica L. Smith,&nbsp;Sixue Zhang,&nbsp;Fahim Ahmad,&nbsp;Shuklendu Karyakarte,&nbsp;Lynn Rasmussen,&nbsp;Victor DeFilippis,&nbsp;Babu Tekwani,&nbsp;Robert Bostwick,&nbsp;Mark J. Suto,&nbsp;Alec J. Hirsch,&nbsp;Thomas E. Morrison,&nbsp;Mark T. Heise,&nbsp;Corinne E. Augelli-Szafran,&nbsp;Daniel N. Streblow,&nbsp;Ashish K. Pathak and Omar Moukha-Chafiq*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0107310.1021/acs.jmedchem.4c01073","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01073https://doi.org/10.1021/acs.jmedchem.4c01073","url":null,"abstract":"<p >2-(Methylthio)-<i>N</i>-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide <b>1</b> was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC₅₀ = 0.6 μM; EC₉₀ = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC₅₀ = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure–activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of <b>1</b> led to the discovery of a new potent inhibitor <i>N</i>-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide <b>26</b>, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC₉₀ of 0.45 μM with considerably improved MLM stability (<i>t</i>_1/2 = 74 min) as compared to <b>1</b>. Mechanism of action studies show that <b>26</b> inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The <i>in vivo</i> efficacy studies of compound <b>26</b> on CHIKV infection in mice are reported.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20858–20878 20858–20878"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842135","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}