ACS Medicinal Chemistry Letters最新文献_第2页

Innovative Protein Degraders for Targeted Cancer and Viral Therapy.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-29 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.5c00030

Robert B Kargbo

引用次数: 0

Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp3 Chemical Space Exploration

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 DOI: 10.1021/acsmedchemlett.4c0059110.1021/acsmedchemlett.4c00591

Brandon M. Taoka, Ning Qi, Zachary G. Brill, Anthony Donofrio, Tao Meng, Yiting Zheng, Bryan S. Matsuura*, Anilkumar G. Nair* and Rohan R. Merchant*,

{"title":"Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp3 Chemical Space Exploration","authors":"Brandon M. Taoka, Ning Qi, Zachary G. Brill, Anthony Donofrio, Tao Meng, Yiting Zheng, Bryan S. Matsuura*, Anilkumar G. Nair* and Rohan R. Merchant*, ","doi":"10.1021/acsmedchemlett.4c0059110.1021/acsmedchemlett.4c00591","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00591https://doi.org/10.1021/acsmedchemlett.4c00591","url":null,"abstract":"From a retrosynthetic standpoint, functionalization or synthesis of heterocyclic cores are fundamental disconnections that chemists make. This manuscript highlights heterocycle synthesis as the strategic bond disconnection by leveraging ubiquitous building blocks, carboxylic acids and amines, for preparation of heterocyclic cores in a library-friendly format. This heterocyclic formation strategy allows medicinal chemists to access much wider chemical space, especially for analogs with higher Fsp3 vs state-of-the-art heterocycle functionalization methods. The direct impact on medicinal chemistry programs is underscored by adapting and miniaturizing the synthesis of N2-indazoles and C2-benzimidazoles to μ-scale parallel medicinal chemistry (PMC) libraries, affording a similar success rate (80%) as venerable Suzuki and Buchwald-Hartwig libraries.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"336–343 336–343"},"PeriodicalIF":3.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394160","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

Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp³ Chemical Space Exploration.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00591

Brandon M Taoka, Ning Qi, Zachary G Brill, Anthony Donofrio, Tao Meng, Yiting Zheng, Bryan S Matsuura, Anilkumar G Nair, Rohan R Merchant

引用次数: 0

Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00529

Zhen Wang, Zong-Zheng Li, Xiao-Min Han, Jing Dong, Ming-Yue Yin, Jie Song, Tao Zhuang, Yuan Wang

{"title":"Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects.","authors":"Zhen Wang, Zong-Zheng Li, Xiao-Min Han, Jing Dong, Ming-Yue Yin, Jie Song, Tao Zhuang, Yuan Wang","doi":"10.1021/acsmedchemlett.4c00529","DOIUrl":"10.1021/acsmedchemlett.4c00529","url":null,"abstract":"Although μ-opioid receptor (MOR) agonists are the most effective drugs for relieving acute pain, nonselective activation of MOR can also lead to serious side effects. There is an urgent need for novel analgesics that can selectively activate MOR under pathological conditions while avoiding side effects under normal physiological conditions. In this study, a series of pH-sensitive 4-propionamide piperidine derivatives were synthesized and evaluated for their MOR activities and antinociceptive effects. Among them, compound 22 showed high pH sensitivity for MOR with a K i pH 7.4/K i pH 6.4 ratio of 6.6. Compound 22 acted as an MOR agonist in the functional test. Compound 22 exhibited good antinociceptive effects in the acetic acid-induced writhing test (ED50 = 1.5 mg/kg) and carrageenan-induced inflammatory pain model (ED50 = 3.3 mg/kg) in mice. Moreover, compound 22 showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound 22 holds promise as a safe candidate for further development as an analgesic with diminished side effects.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"285-293"},"PeriodicalIF":3.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447355","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

AMP-Activated Protein Kinase Activators as Therapeutic Targets To Treat Heart Failure and Diseases That Can Benefit from Improved Muscular Performance.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.5c00025

Ahmed F Abdel-Magid

引用次数: 0

Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-27 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.5c00026

Ahmed F Abdel-Magid

引用次数: 0

Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors as Potential Treatment for Several Inflammatory and Neurodegenerative Diseases 受体相互作用蛋白激酶 1 (RIPK1) 抑制剂有望治疗多种炎症和神经退行性疾病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1021/acsmedchemlett.5c0002610.1021/acsmedchemlett.5c00026

Ahmed F. Abdel-Magid*,

引用次数: 0

Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1021/acsmedchemlett.4c0052910.1021/acsmedchemlett.4c00529

Zhen Wang, Zong-Zheng Li, Xiao-Min Han, Jing Dong, Ming-Yue Yin, Jie Song, Tao Zhuang* and Yuan Wang*,

{"title":"Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects","authors":"Zhen Wang, Zong-Zheng Li, Xiao-Min Han, Jing Dong, Ming-Yue Yin, Jie Song, Tao Zhuang* and Yuan Wang*, ","doi":"10.1021/acsmedchemlett.4c0052910.1021/acsmedchemlett.4c00529","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00529https://doi.org/10.1021/acsmedchemlett.4c00529","url":null,"abstract":"Although μ-opioid receptor (MOR) agonists are the most effective drugs for relieving acute pain, nonselective activation of MOR can also lead to serious side effects. There is an urgent need for novel analgesics that can selectively activate MOR under pathological conditions while avoiding side effects under normal physiological conditions. In this study, a series of pH-sensitive 4-propionamide piperidine derivatives were synthesized and evaluated for their MOR activities and antinociceptive effects. Among them, compound 22 showed high pH sensitivity for MOR with a Ki pH 7.4/Ki pH 6.4 ratio of 6.6. Compound 22 acted as an MOR agonist in the functional test. Compound 22 exhibited good antinociceptive effects in the acetic acid-induced writhing test (ED50 = 1.5 mg/kg) and carrageenan-induced inflammatory pain model (ED50 = 3.3 mg/kg) in mice. Moreover, compound 22 showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound 22 holds promise as a safe candidate for further development as an analgesic with diminished side effects.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"285–293 285–293"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397280","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

AMP-Activated Protein Kinase Activators as Therapeutic Targets To Treat Heart Failure and Diseases That Can Benefit from Improved Muscular Performance

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1021/acsmedchemlett.5c0002510.1021/acsmedchemlett.5c00025

Ahmed F. Abdel-Magid*,

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 DOI: 10.1021/acsmedchemlett.4c0050510.1021/acsmedchemlett.4c00505

Yaëlle Fischer, Ruel Cedeno*, Dhoha Triki, Bertrand Vivet and 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 and Philippe Schambel, ","doi":"10.1021/acsmedchemlett.4c0050510.1021/acsmedchemlett.4c00505","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00505https://doi.org/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":"263–270 263–270"},"PeriodicalIF":3.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397273","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