ACS Medicinal Chemistry Letters最新文献

Announcing the 2024 ACS Division of Medicinal Chemistry Award Recipients: Celebrating Excellence in Medicinal Chemistry 宣布2024年ACS药物化学部门获奖者：庆祝药物化学卓越

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-12 DOI: 10.1021/acsmedchemlett.5c0025710.1021/acsmedchemlett.5c00257

Lori Ferrins, and , Paul C. Trippier,

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In this Issue Volume 16, Issue 6 第16卷，第6期

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-12 DOI: 10.1021/acsmedchemlett.5c0029310.1021/acsmedchemlett.5c00293

Simone V. Bigi-Botterill,

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Novel Substituted Pyrazoles as 5-HT1A Agonists for Treating Neuropsychiatric Diseases 新型取代吡唑作为5-HT1A激动剂治疗神经精神疾病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI: 10.1021/acsmedchemlett.5c0030610.1021/acsmedchemlett.5c00306

Ram W. Sabnis*,

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Suzuki–Miyaura Coupling of Pinacolboronic Esters Catalyzed by a Well-Defined Palladium N-Heterocyclic Carbene (NHC) Catalyst 一种定义良好的n -杂环钯（NHC）催化剂催化的双硼酸酯的Suzuki-Miyaura偶联

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI: 10.1021/acsmedchemlett.5c0020610.1021/acsmedchemlett.5c00206

Aleksei A. Logvinov, Geert Rombouts, Matthieu Jouffroy* and Steven P. Nolan*,

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Pyrroloquinolone-Based Compounds as a Novel Antimycobacterial Chemotype 吡咯喹诺酮类化合物作为一种新型抗细菌化学型

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI: 10.1021/acsmedchemlett.5c0018310.1021/acsmedchemlett.5c00183

Marta Clariano, Diogo Nunes, Daniela Canudo, Daniela Maçãs, Bruno J. L. Castro, Audrey Jordaan, Pedro Gomes, Anna Contini, João Perdigão, Isabel Portugal, Margarida Madureira, Digby F. Warner, Marco Pieroni, Maria de Jesus Perry* and Francisca Lopes*,

{"title":"Pyrroloquinolone-Based Compounds as a Novel Antimycobacterial Chemotype","authors":"Marta Clariano, Diogo Nunes, Daniela Canudo, Daniela Maçãs, Bruno J. L. Castro, Audrey Jordaan, Pedro Gomes, Anna Contini, João Perdigão, Isabel Portugal, Margarida Madureira, Digby F. Warner, Marco Pieroni, Maria de Jesus Perry* and Francisca Lopes*, ","doi":"10.1021/acsmedchemlett.5c0018310.1021/acsmedchemlett.5c00183","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00183https://doi.org/10.1021/acsmedchemlett.5c00183","url":null,"abstract":"Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains the world’s most lethal infectious disease, posing an uncontained health challenge. The major hurdles are the long treatments and low patient compliance that leads to the appearance of resistance, as well as the lack of drugs that effectively tackle the latent infections. Herein we report the development of compounds with the ability to target the electron transport chain of Mtb by inhibiting cytochrome bcc (cyt-bcc) (7a–i) and additionally being capable of inhibiting cytochrome bd (cyt-bd) (7j and 7k). We present the synthesis, determination of physicochemical properties, evaluation of the antibacterial activity, and cytotoxicity assessment of pyrroloquinolone-based compounds. The antibacterial evaluation of 7a–k showed selectivity toward mycobacteria, and the results identify cyt-bcc as their target. Compounds 7j and 7k presented promising results against Mtb and good physicochemical properties. Cytotoxicity assays revealed a good safety profile regarding the toxicity for human cell lines.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1139–1146 1139–1146"},"PeriodicalIF":3.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261042","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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New Multiparameter Index Is a Strong Predictor of Oral Bioavailability for Heterobifunctional Degraders 新的多参数指标是异双功能降解剂口服生物利用度的有力预测指标

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI: 10.1021/acsmedchemlett.5c0015610.1021/acsmedchemlett.5c00156

Javier L. Baylon*, Matthew J. Chalkley, Tony Siu, Wilson Shou, Yongnian Sun, Xianmei Cai, Anthony Paiva, Shivani Patel, Tatyana Zvyaga and Dahlia R. Weiss,

{"title":"New Multiparameter Index Is a Strong Predictor of Oral Bioavailability for Heterobifunctional Degraders","authors":"Javier L. Baylon*, Matthew J. Chalkley, Tony Siu, Wilson Shou, Yongnian Sun, Xianmei Cai, Anthony Paiva, Shivani Patel, Tatyana Zvyaga and Dahlia R. Weiss, ","doi":"10.1021/acsmedchemlett.5c0015610.1021/acsmedchemlett.5c00156","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00156https://doi.org/10.1021/acsmedchemlett.5c00156","url":null,"abstract":"Ligand-directed degraders (LDDs) are heterobifunctional molecules that degrade proteins by engaging the ubiquitin-protein-ligase (E3) system. LDDs (also known as proteolysis-targeting chimeras) consist of a target-engaging moiety, an E3 ligase-binding moiety, and a bridging linker. Due to their size and physicochemical complexity, these molecules do not adhere to well-established rules of lead optimization. Achieving oral bioavailability remains a key challenge in the optimization of LDDs as therapeutic agents. In this study, we build on the previously established Balanced Permeability Index (BPI) (a metric that integrates size, polarity, and lipophilicity) by incorporating an additional descriptor to account for molecular shape. Our new combined metric, termed Bifunctional Bioavailability Index (BBI), can differentiate oral bioavailability of LDDs in our data set more effectively than polarity, lipophilicity, or size separately. Notably, BBI is also more effective than in vitro cell permeability assays in predicting orally bioavailable LDDs. These results support the use of BBI as a computational tool for designing and optimizing bioavailable bifunctional degraders.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1108–1113 1108–1113"},"PeriodicalIF":3.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261087","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 Bicyclic Heterocycles as MRGPRX2 Antagonists for Treating Inflammatory Diseases 新型双环杂环作为MRGPRX2拮抗剂治疗炎性疾病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-02 DOI: 10.1021/acsmedchemlett.5c0030510.1021/acsmedchemlett.5c00305

Ram W. Sabnis*,

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Triazine Macrocycle Libraries: Synthesis, logD Prediction, and a Surprisingly Hydrophobic, Membrane-Permeable Diamine 三嗪大环文库：合成，logD预测，和一个令人惊讶的疏水，膜透性二胺

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-02 DOI: 10.1021/acsmedchemlett.5c0007810.1021/acsmedchemlett.5c00078

Gretel A. Stokes, Casey J. Patterson-Gardner, Alexander M. Engstrom, Alexander J. Menke, K. Harsha Vardhan Reddy, R. Scott Lokey and Eric E. Simanek*,

{"title":"Triazine Macrocycle Libraries: Synthesis, logD Prediction, and a Surprisingly Hydrophobic, Membrane-Permeable Diamine","authors":"Gretel A. Stokes, Casey J. Patterson-Gardner, Alexander M. Engstrom, Alexander J. Menke, K. Harsha Vardhan Reddy, R. Scott Lokey and Eric E. Simanek*, ","doi":"10.1021/acsmedchemlett.5c0007810.1021/acsmedchemlett.5c00078","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00078https://doi.org/10.1021/acsmedchemlett.5c00078","url":null,"abstract":"A library of triazine macrocycles was obtained to evaluate strategies for predicting lipophilicity using additive algorithms. Two synthetic routes were examined. While both were successful, one proved amenable to solution-phase library synthesis. The octanol–water partition coefficients (logP) were measured using reverse-phase HPLC at pH 10. When experimental and computed values (AlogP) are compared, a linear correlation is observed. That is, while additive algorithms underestimate hydrophobicity by a factor of 100, a simple correction yields accurate predictions. Two macrocycles showed anomalous hydrophobicities at high pH that were borne out in membrane transit (PAMPA) studies. Homodimers containing two primary amines were more hydrophobic than the corresponding heterodimers containing a single amine and a hydrophobic group. Structural analysis and computation provide a rationale for this behavior: the amines engage in an intramolecular hydrogen bond.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1017–1023 1017–1023"},"PeriodicalIF":3.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260870","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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A Miniaturized Chemical High Throughput Experimentation Plate to Enable Late-Stage Oxidation Screening and Scale-up 一个小型化的化学高通量实验板，使后期氧化筛选和放大

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-06-02 DOI: 10.1021/acsmedchemlett.5c0017510.1021/acsmedchemlett.5c00175

Javier Izquierdo-Ferrer*, Mary E. Bellizzi, Noah Tu, Andrew Bogdan and Ying Wang,

{"title":"A Miniaturized Chemical High Throughput Experimentation Plate to Enable Late-Stage Oxidation Screening and Scale-up","authors":"Javier Izquierdo-Ferrer*, Mary E. Bellizzi, Noah Tu, Andrew Bogdan and Ying Wang, ","doi":"10.1021/acsmedchemlett.5c0017510.1021/acsmedchemlett.5c00175","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00175https://doi.org/10.1021/acsmedchemlett.5c00175","url":null,"abstract":"Chemical methods for Late-Stage Oxidation (LSO) of advanced and complex molecules remain a highly relevant topic, with new and improved methods being reported annually. Despite the growing number of methodologies, the scope and limitations of these methods in bioactive molecules is largely unknown. We have designed a High-Throughput Experimentation (HTE) plate based on validated LSO methods, capable of screening compounds using only a few milligrams, to enhance our Late-Stage Functionalization (LSF) platform. Various projects at AbbVie have benefited from this plate, generating essential data for programs and creating new analogs for comprehensive Structure–Activity Relationship (SAR) analysis. We demonstrated the transformative capabilities of this approach by screening nine well-known drugs and analyzed the oxidized derivatives. This report highlights how this overlooked transformation can be an effective synthetic tool for medicinal chemistry.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"916–924 916–924"},"PeriodicalIF":3.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261079","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 2,6,9-Trisubstituted Purines as CDK2 Inhibitors for Treating Cancers 新型2,6,9-三取代嘌呤作为CDK2抑制剂治疗癌症

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-05-30 DOI: 10.1021/acsmedchemlett.5c0028210.1021/acsmedchemlett.5c00282

Jian Rong, and , Steven H. Liang*,

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