ACS Medicinal Chemistry Letters最新文献_第3页

Potential of Histone Deacetylase 6 Inhibitors as a Treatment of Neurodegenerative Diseases.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.5c00024

Ahmed F Abdel-Magid

引用次数: 0

Use of Aldehyde-Alkyne-Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00531

Andrew McGown, Vesna Vetma, Damien Crepin, Yan Lin, Claire Adcock, Conner Craigon, Jordan Nafie, Daniel von Emloh, Léa Sutton, Kiera Bailey, Lewis Edmunds, Manvendra Sharma, Jonathan D Wilden, Simon J Coles, Graham J Tizzard, William Farnaby, Alessio Ciulli, George E Kostakis, John Spencer

引用次数: 0

Use of Aldehyde–Alkyne–Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers 利用醛-炔-胺偶联生成药物化学相关连接体

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 DOI: 10.1021/acsmedchemlett.4c0053110.1021/acsmedchemlett.4c00531

Andrew McGown*, Vesna Vetma, Damien Crepin, Yan Lin, Claire Adcock, Conner Craigon, Jordan Nafie, Daniel von Emloh, Léa Sutton, Kiera Bailey, Lewis Edmunds, Manvendra Sharma, Jonathan D. Wilden, Simon J. Coles, Graham J. Tizzard, William Farnaby, Alessio Ciulli, George E. Kostakis and John Spencer*,

引用次数: 0

Development of the Pyrido[2,3-d]pyrimidin-7(8H)-one Scaffold toward Potent and Selective NUAK1 Inhibitors.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00579

Timothy P C Rooney, Gregory G Aldred, David Winpenny, Helen Scott, Henriette M G Willems, Iryna Voytyuk, Jonathan H Clarke, Helen K Boffey, Stephen P Andrews, John Skidmore

引用次数: 0

Evaluating the Diversity and Target Addressability of DELs using Scaffold Analysis and Machine Learning.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00505

Yaëlle Fischer, Ruel Cedeno, Dhoha Triki, Bertrand Vivet, Philippe Schambel

{"title":"Evaluating the Diversity and Target Addressability of DELs using Scaffold Analysis and Machine Learning.","authors":"Yaëlle Fischer, Ruel Cedeno, Dhoha Triki, Bertrand Vivet, Philippe Schambel","doi":"10.1021/acsmedchemlett.4c00505","DOIUrl":"10.1021/acsmedchemlett.4c00505","url":null,"abstract":"DELs enable efficient experimental screening of vast combinatorial libraries, offering a powerful platform for drug discovery. Apart from ensuring the druglike physicochemical properties, other key parameters to maximize the success rate of DEL designs include the scaffold diversity and target addressability. While several tools exist to assess chemical diversity, a dedicated computational approach combining both parameters is currently lacking. Here, we present a cheminformatics tool leveraging scaffold analysis and machine learning to evaluate both scaffold diversity and target-orientedness. Using two in-house libraries as a case study, we demonstrate the workflow's ability to distinguish between generalist and focused libraries. This capability can guide medicinal chemists in selecting libraries tailored for specific objectives, such as hit-finding or hit-optimization. To facilitate utilization, this tool is freely available both as a web application and as a Python script at https://github.com/novalixofficial/NovaWebApp.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"263-270"},"PeriodicalIF":3.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Potential of Histone Deacetylase 6 Inhibitors as a Treatment of Neurodegenerative Diseases

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 DOI: 10.1021/acsmedchemlett.5c0002410.1021/acsmedchemlett.5c00024

Ahmed F. Abdel-Magid*,

引用次数: 0

Development of the Pyrido[2,3-d]pyrimidin-7(8H)-one Scaffold toward Potent and Selective NUAK1 Inhibitors 开发吡啶并[2,3-d]嘧啶-7(8H)-酮支架，研制强效选择性 NUAK1 抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 DOI: 10.1021/acsmedchemlett.4c0057910.1021/acsmedchemlett.4c00579

Timothy P. C. Rooney, Gregory G. Aldred, David Winpenny, Helen Scott, Henriette M. G. Willems, Iryna Voytyuk, Jonathan H. Clarke, Helen K. Boffey*, Stephen P. Andrews and John Skidmore*,

{"title":"Development of the Pyrido[2,3-d]pyrimidin-7(8H)-one Scaffold toward Potent and Selective NUAK1 Inhibitors","authors":"Timothy P. C. Rooney, Gregory G. Aldred, David Winpenny, Helen Scott, Henriette M. G. Willems, Iryna Voytyuk, Jonathan H. Clarke, Helen K. Boffey*, Stephen P. Andrews and John Skidmore*, ","doi":"10.1021/acsmedchemlett.4c0057910.1021/acsmedchemlett.4c00579","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00579https://doi.org/10.1021/acsmedchemlett.4c00579","url":null,"abstract":"The protein kinase NUAK1 has been implicated in various biological functions including cell adhesion, migration and proliferation. Genetic reduction of NUAK1 expression has notably been shown to lower total levels of human tau in a tauopathy mouse model, identifying this kinase as a potential therapeutic target for neurodegenerative disease. In this paper, we describe improvement of the NUAK1 potency, kinase-selectivity and pharmacokinetic properties of the brain-penetrant but unselective CDK4/CDK6/NUAK1 inhibitor ON123300. Through a scaffold-optimization approach we have identified different chemotypes delivering NUAK1 inhibition with improved potency and selectivity over CDK kinases compared with ON123300. We present ADME profiling and in vivo pharmacokinetic data for these compounds.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"327–335 327–335"},"PeriodicalIF":3.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00579","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Novel Triazine Derivatives as NLRP3 Inhibitors for Treating Asthma or COPD

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-24 DOI: 10.1021/acsmedchemlett.5c0002010.1021/acsmedchemlett.5c00020

Ram W. Sabnis*,

引用次数: 0

Protection against Amyloid-β Aggregation and Ferroptosis/Oxytosis Toxicity by Arylpyrazolones: Alzheimer's Disease Therapeutics.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-24 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00530

Pedro Soares, Mizzanoor Rahaman, Pamela Maher, Richard B Silverman

{"title":"Protection against Amyloid-β Aggregation and Ferroptosis/Oxytosis Toxicity by Arylpyrazolones: Alzheimer's Disease Therapeutics.","authors":"Pedro Soares, Mizzanoor Rahaman, Pamela Maher, Richard B Silverman","doi":"10.1021/acsmedchemlett.4c00530","DOIUrl":"10.1021/acsmedchemlett.4c00530","url":null,"abstract":"Alzheimer's disease (AD) incurs heavy costs for both the population and health systems. Nevertheless, the drugs available only provide minimal symptomatic management without much impact on the patients' quality of life. The multifactorial character of AD suggests that the development of new therapies modulating multiple biological targets contributing to disease progression will more efficiently treat the disease. The success of therapies targeting amyloid-beta oligomers suggests this is a valid approach for the development of more efficacious therapies for AD. Here, we report the design and evaluation of a series of arylpyrazolone compounds for their activity against Aβ aggregation toxicity and oxidative stress. The lead compound (1) has an EC50 value of 270 nM, good blood-brain barrier permeation in vivo and promising bioavailability. This study demonstrates the potential of these arylpyrazolones as novel, and potentially more effective, multifactorial therapies for AD.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"294-300"},"PeriodicalIF":3.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Protection against Amyloid-β Aggregation and Ferroptosis/Oxytosis Toxicity by Arylpyrazolones: Alzheimer’s Disease Therapeutics 芳基吡唑酮类药物对淀粉样蛋白-β聚集和铁氧化/氧化毒性的保护作用：阿尔茨海默病治疗药物

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-24 DOI: 10.1021/acsmedchemlett.4c0053010.1021/acsmedchemlett.4c00530

Pedro Soares, Mizzanoor Rahaman, Pamela Maher and Richard B. Silverman*,

{"title":"Protection against Amyloid-β Aggregation and Ferroptosis/Oxytosis Toxicity by Arylpyrazolones: Alzheimer’s Disease Therapeutics","authors":"Pedro Soares, Mizzanoor Rahaman, Pamela Maher and Richard B. Silverman*, ","doi":"10.1021/acsmedchemlett.4c0053010.1021/acsmedchemlett.4c00530","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00530https://doi.org/10.1021/acsmedchemlett.4c00530","url":null,"abstract":"Alzheimer’s disease (AD) incurs heavy costs for both the population and health systems. Nevertheless, the drugs available only provide minimal symptomatic management without much impact on the patients’ quality of life. The multifactorial character of AD suggests that the development of new therapies modulating multiple biological targets contributing to disease progression will more efficiently treat the disease. The success of therapies targeting amyloid-beta oligomers suggests this is a valid approach for the development of more efficacious therapies for AD. Here, we report the design and evaluation of a series of arylpyrazolone compounds for their activity against Aβ aggregation toxicity and oxidative stress. The lead compound (1) has an EC50 value of 270 nM, good blood-brain barrier permeation in vivo and promising bioavailability. This study demonstrates the potential of these arylpyrazolones as novel, and potentially more effective, multifactorial therapies for AD.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"294–300 294–300"},"PeriodicalIF":3.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397316","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