ACS Medicinal Chemistry Letters最新文献_第2页

Correction to “Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting” 更正“第四代EGFR抑制剂的结构研究揭示了选择性T790M和C797S靶向的见解”

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-09 DOI: 10.1021/acsmedchemlett.6c00455

Tahereh Damghani, Shenghan Song, Kaly S. Lin, Jianing Li, David E. Heppner

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Synthesis of 1,3-Dihydro-2,1-benzisoxazoles by Intramolecular C–N Coupling: Evaluation as an Indane Bioisostere 分子内C-N偶联合成1,3-二氢-2,1-苯并异恶唑：作为吲哚类生物异构体的评价

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-27 DOI: 10.1021/acsmedchemlett.6c00429

Thomas D. Beckler, David Crich

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Correction to “Discovery of a Colon-Targeted Prodrug As an Escherichia coli Biofilm Inhibitor for Treating Inflammatory Bowel Disease” 更正“发现结肠靶向前药作为治疗炎症性肠病的大肠杆菌生物膜抑制剂”

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-03 DOI: 10.1021/acsmedchemlett.6c00463

Takahisa Shimizu, Keiko Tago, Miki Yokoyama, Koichi Nakamura, Sumika Tokieda-Tanoue, Akemi Kita, Shojiro Miyazaki

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Minimalist d-Tripeptide Prodrug Mimetics of the Myostatin Prodomain as Selective Inhibitors of Skeletal Muscle Atrophy Signaling 肌生长抑制素前域的极简d-三肽前药模拟物作为骨骼肌萎缩信号传导的选择性抑制剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-04 DOI: 10.1021/acsmedchemlett.6c00358

Jae Ho Shim, Ji Yeon Lee, Jihye Han, Hyeon Soo Kim

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How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties 吗啡类阿片拮抗剂的细微分子差异如何影响其理化和体外ADME性能

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-10 DOI: 10.1021/acsmedchemlett.6c00324

Sigal Saphier, Ada Wenger, Alexander Pevzner, Dina Yeffet, Boris Smolkin, Naama Lifshin-Karton, Shlomi Elias, Yoav Eichen, Galit Parvari, Shahaf Katalan, Yossi Zafrani

{"title":"How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties","authors":"Sigal Saphier, Ada Wenger, Alexander Pevzner, Dina Yeffet, Boris Smolkin, Naama Lifshin-Karton, Shlomi Elias, Yoav Eichen, Galit Parvari, Shahaf Katalan, Yossi Zafrani","doi":"10.1021/acsmedchemlett.6c00324","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00324","url":null,"abstract":"Naloxone, naltrexone and nalmefene are closely relatedmorphinanantagonists with comparable affinities to the μ-opioid receptor(MOR) but markedly different pharmacokinetics (PK) and metabolic fate.In this study, we evaluated their pharmacologically-relevant molecular/physicochemicalproperties, PAMPA-BBB (Parallel Artificial Membrane Permeability Assayfor the Blood-Brain Barrier) permeability and in vitro metabolic stabilityto determine how subtle structural differences influence ADME-relevantproperties. Moreover, the pharmacologically-relevant properties ofthese three antagonists were compared with those of the best-knownsynthetic opioid agonist, fentanyl. We found that the methyl-cyclopropylversus allyl head group, as well as the C6-carbonyl versus C6-ethenylgroup, dramatically influence all the above-mentioned properties andhelp explain the in vivo observed differences between these antagonists.These results may support the rational design of new and improvedopioid antagonists with optimized PK properties.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2197–2205"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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Cannabinol β-O-Glucoside Inhibitors of the Keap1-Nrf2 Interaction: A Novel Therapeutic Strategy for Parkinson’s Disease 大麻酚β- o -葡萄糖苷抑制剂Keap1-Nrf2相互作用：帕金森病的新治疗策略

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-01 DOI: 10.1021/acsmedchemlett.6c00156

Prashant Deshmukh, Snehal Aouti, Ashok Sridhar, Padmini Kommu, Amrutha K, Sarika Singh, Yedukondalu Nalli, Aneeza Noor, Bharath M. M. Srinivas, Asif Ali, Balasundaram Padmanabhan

{"title":"Cannabinol β-O-Glucoside Inhibitors of the Keap1-Nrf2 Interaction: A Novel Therapeutic Strategy for Parkinson’s Disease","authors":"Prashant Deshmukh, Snehal Aouti, Ashok Sridhar, Padmini Kommu, Amrutha K, Sarika Singh, Yedukondalu Nalli, Aneeza Noor, Bharath M. M. Srinivas, Asif Ali, Balasundaram Padmanabhan","doi":"10.1021/acsmedchemlett.6c00156","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00156","url":null,"abstract":"Oxidative stress and xenobiotic exposure disrupt redoxhomeostasisand contribute to neurodegenerative disease progression. The Keap1-Nrf2-AREpathway is a key antioxidant defense mechanism, in which Nrf2 activatescytoprotective gene expression. Because disrupting the Keap1-Nrf2interaction can enhance antioxidant responses, we assessed modifiedCannabis sativa cannabinoids bearing C- and O-β-d-glucosidesas potential Keap1 inhibitors. Building on our earlier fractionationand derivatization work, these compounds were evaluated for bindingto the Keap1 BTB and KDC domains and for activation of Nrf2-mediatedresponses using in vitro and in silico methods. In a Parkinson’s disease model, CS-11 (4a) showed the strongest neuroprotective effect, with an EC50 of 100 nM. Treatment significantly increased cytoprotective geneexpression, indicating enhanced Nrf2 transcriptional activity. CS-11(4a) also restored tyrosine hydroxylase levels and protected dopaminergicneurons from cell death. Computational analyses supported its Keap1-targetingactivity, identifying CS-11 (4a) as a promising Parkinson’sdisease therapeutic candidate.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2127–2139"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Decoupling Neuroprotection from MAO Inhibition via Indane-to-Azaindane Bioisosteric Replacement of Rasagiline 通过茚一氮丹生物等构替代雷沙吉兰，将神经保护从MAO抑制中解耦

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-12 DOI: 10.1021/acsmedchemlett.6c00407

Ivo E. Sampaio-Dias, Sara C. Silva-Reis, Xavier C. Correia, Hugo F. Costa-Almeida, Maria B. Igreja-Cardoso, Gabriel M. Azevedo, Vera M. Costa, Damijan Knez, Stanislav Gobec, José E. Rodríguez-Borges

{"title":"Decoupling Neuroprotection from MAO Inhibition via Indane-to-Azaindane Bioisosteric Replacement of Rasagiline","authors":"Ivo E. Sampaio-Dias, Sara C. Silva-Reis, Xavier C. Correia, Hugo F. Costa-Almeida, Maria B. Igreja-Cardoso, Gabriel M. Azevedo, Vera M. Costa, Damijan Knez, Stanislav Gobec, José E. Rodríguez-Borges","doi":"10.1021/acsmedchemlett.6c00407","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00407","url":null,"abstract":"Rasagiline is a monoamineoxidase B (MAO-B) inhibitorwith neuroprotectiveeffects, whose dependence on MAO-B inhibition remains unclear. Here, indane-to-azaindane rasagiline isosteres (rac-2a and rac-2b) were developedto investigate whether neuroprotection can be decoupled from MAO-Binhibition. Direct regioselective oxidation of 4-azaindane catalyzedby Mn(OAc)2/tBuOOH affordedthe key 4-azaindan-1-one intermediate (6a). In paraquat-insulteddopaminergic differentiated SH-SY5Y cells, both analogs showed neuroprotectionat 10 and 100 μM, with rac-2b outperformingrasagiline. The azaindane analogs displayed markedly reduced MAO-Binhibition and no time-dependent inhibition. These findings demonstratethat rasagiline neuroprotection can be dissociated from MAO-B inhibition,supporting azaindane bioisosterism for exploring MAO-independent neuroprotection.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2251–2259"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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Novel Compounds as SMARCA2 Inhibitors for Treating Non-Small Cell Lung Cancer 新化合物作为SMARCA2抑制剂治疗非小细胞肺癌

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-26 DOI: 10.1021/acsmedchemlett.6c00489

Ram W. Sabnis

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Scope and Differences between ACS Medicinal Chemistry Letters and Journal of Medicinal Chemistry ACS药物化学快报与《药物化学杂志》的范围与差异

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 DOI: 10.1021/acsmedchemlett.6c00476

Kelly Chibale, Craig W. Lindsley

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Design, Synthesis, and Antimicrobial Activity of Novel Cyt-bd Inhibitors Targeting Energy Compensation in Mycobacterium tuberculosis 针对结核分枝杆菌能量补偿的新型Cyt-bd抑制剂的设计、合成和抗菌活性研究

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-18 DOI: 10.1021/acsmedchemlett.6c00310

Qiao Qin, Zhuoheng Liu, Chen-Yi Cheung, Jinxu Xu, Sadaf Kalsum, Hang Yu, Maria Lerm, Hongri Gong, Matthew McNeil, Gregory M. Cook, Susanna Brighenti, Yang Zhou, Xiaoyun Lu

{"title":"Design, Synthesis, and Antimicrobial Activity of Novel Cyt-bd Inhibitors Targeting Energy Compensation in Mycobacterium tuberculosis","authors":"Qiao Qin, Zhuoheng Liu, Chen-Yi Cheung, Jinxu Xu, Sadaf Kalsum, Hang Yu, Maria Lerm, Hongri Gong, Matthew McNeil, Gregory M. Cook, Susanna Brighenti, Yang Zhou, Xiaoyun Lu","doi":"10.1021/acsmedchemlett.6c00310","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00310","url":null,"abstract":"Drug-resistant Mycobacterium tuberculosis (Mtb) poses a growing threat, necessitating newtherapeuticstrategies. The cytochrome bcc-aa3 oxidase (Cyt-bcc) is an attractivetarget, yet single-agent inhibition fails owing to compensation bythe alternative cytochrome bd terminal oxidase (Cyt-bd). Herein, we describe a structure–activity relationship(SAR) study starting from the previously identified Cyt-bd inhibitor 12, leading to the discovery of 17aa (YH-685). YH-685 potently inhibits Cyt-bcc deficient Mycobacterium smegmatis (Δbcc) with a MIC of 0.8 μM and suppresses Cyt-bd dependent oxygen consumption in inverted membrane vesicleswith an IC50 of 0.45 μM. When combined with the Cyt-bcc inhibitor TB47, YH-685 enhanced inhibitionof virulent Mtb H37Rv, reducing both planktonic growthand intracellular bacterial burdens in human macrophages, as assessedby high-content imaging. Under the tested in vitro conditions, this combination achieved growth inhibition comparableto standard regimens rifampicin–isoniazid and bedaquiline.Our study supports co-targeting Cyt-bd and Cyt-bcc as a therapeutic strategy for drug-resistant tuberculosis.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2182–2190"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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