ACS Medicinal Chemistry Letters最新文献_第8页

Novel Heterocyclic Pyrimidine Derivatives as GSK3α Inhibitors 新型杂环嘧啶衍生物作为GSK3α抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-07 DOI: 10.1021/acsmedchemlett.5c0015910.1021/acsmedchemlett.5c00159

Yinlong Li, and , Steven H. Liang*,

引用次数: 0

Macrocyclization: Enhancing Drug-like Properties of Discoidin Domain Receptor Kinase Inhibitors. 大环化：增强盘状圆盘蛋白结构域受体激酶抑制剂的药物样特性。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-07 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.4c00611

Laura Carzaniga, Roberta Mazzucato, Valentina Mileo, Andrea Rizzi, Maura Vallaro, Giuseppe Ermondi, Silvia Cattani, Andrea Secchi, Giulia Caron

{"title":"Macrocyclization: Enhancing Drug-like Properties of Discoidin Domain Receptor Kinase Inhibitors.","authors":"Laura Carzaniga, Roberta Mazzucato, Valentina Mileo, Andrea Rizzi, Maura Vallaro, Giuseppe Ermondi, Silvia Cattani, Andrea Secchi, Giulia Caron","doi":"10.1021/acsmedchemlett.4c00611","DOIUrl":"10.1021/acsmedchemlett.4c00611","url":null,"abstract":"Macrocyclization, a well-established strategy for developing ligands against challenging drug targets, was employed to design macrocyclic alternatives to a linear discoidin domain receptor (DDR) inhibitor (1) with potential applications in treating fibrotic diseases. This study aimed to enhance the drug-like profile of 1 through innovative design strategies encompassing molecular docking and chameleonicity considerations. These efforts resulted in the synthesis of matched pairs of macrocycles differing in flexibility and linker features. Compound 5a emerged as a promising lead, exhibiting nanomolar-range activity, significantly improved solubility, and excellent permeability. Comprehensive experimental physicochemical characterization further highlighted the modest impact of ionization, the major role played by lipophilicity (but not polarity) in driving permeability of the investigated matched pairs, and the limitations of traditional 2D computational descriptors in predicting macrocycle ADME-related properties.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"784-789"},"PeriodicalIF":3.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951012","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 Tricyclic Compounds as GSK3 Inhibitors 新型三环化合物作为GSK3抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-04 DOI: 10.1021/acsmedchemlett.5c0016210.1021/acsmedchemlett.5c00162

Yinlong Li, and , Steven H. Liang*,

引用次数: 0

Novel 2-Pyrrolidone Derivatives as Negative Allosteric Modulators of GluN2B-Containing NMDA Receptors. 新型2-吡咯烷酮衍生物作为glun2b -含NMDA受体的负变构调节剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-04 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00157

Yinlong Li, Steven H Liang

引用次数: 0

Novel 2-Pyrrolidone Derivatives as Negative Allosteric Modulators of GluN2B-Containing NMDA Receptors 新型2-吡咯烷酮衍生物作为glun2b -含NMDA受体的负变构调节剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-04 DOI: 10.1021/acsmedchemlett.5c0015710.1021/acsmedchemlett.5c00157

Yinlong Li, and , Steven H. Liang*,

引用次数: 0

Novel Tricyclic Compounds as GSK3 Inhibitors. 新型三环化合物作为GSK3抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-04 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00162

Yinlong Li, Steven H Liang

引用次数: 0

Discovery of a Novel [6–6–5–5–6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold 一种新型[6-6-5 - 6]五环四氢环五酞嗪酮作为PARP抑制剂支架的发现

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-03 DOI: 10.1021/acsmedchemlett.4c0060310.1021/acsmedchemlett.4c00603

Yagmur U. Doruk, Morgan E. Diolaiti, Alan Ashworth* and Tanaji T. Talele*,

{"title":"Discovery of a Novel [6–6–5–5–6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold","authors":"Yagmur U. Doruk, Morgan E. Diolaiti, Alan Ashworth* and Tanaji T. Talele*, ","doi":"10.1021/acsmedchemlett.4c0060310.1021/acsmedchemlett.4c00603","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00603https://doi.org/10.1021/acsmedchemlett.4c00603","url":null,"abstract":"Inhibitors of poly(ADP-ribose) polymerases (PARPs) have revolutionized the treatment of cancers with DNA repair deficiencies. Here we describe the structure-based discovery and synthesis of 6–6–5–5–6-fused pentacyclic scaffolds 5 and cis-(±)-6 as a novel class of PARP1 inhibitors. Chiral supercritical fluid chromatographic separation of cis-(±)-6 afforded inactive ent-6_P1 and active ent-6_P2. Compound 5 (P-gp ER = 0.9) and ent-6_P2 (P-gp ER = 1.1) demonstrated good Caco-2 permeability and are not actively effluxed by ABC transporters. In vitro analysis in HEK293T cells found that 5, cis-(±)-6, and ent-6_P2 showed near complete inhibition of PARP1 activity at 10 μM. Furthermore, compounds 5, cis-(±)-6, and ent-6_P2 displayed selective cytotoxic activity in BRCA mutant cancer cells but not isogenic BRCA-proficient cells. Taken together, 5 and ent-6_P2 define a novel class of lead PARP inhibitors for further development.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"776–783 776–783"},"PeriodicalIF":3.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917046","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

Discovery of a Novel [6-6-5-5-6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold. 一种新型[6-6-5- 6]五环四氢环五酞嗪酮作为PARP抑制剂支架的发现。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-03 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.4c00603

Yagmur U Doruk, Morgan E Diolaiti, Alan Ashworth, Tanaji T Talele

{"title":"Discovery of a Novel [6-6-5-5-6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold.","authors":"Yagmur U Doruk, Morgan E Diolaiti, Alan Ashworth, Tanaji T Talele","doi":"10.1021/acsmedchemlett.4c00603","DOIUrl":"10.1021/acsmedchemlett.4c00603","url":null,"abstract":"Inhibitors of poly(ADP-ribose) polymerases (PARPs) have revolutionized the treatment of cancers with DNA repair deficiencies. Here we describe the structure-based discovery and synthesis of 6-6-5-5-6-fused pentacyclic scaffolds 5 and cis-(±)-6 as a novel class of PARP1 inhibitors. Chiral supercritical fluid chromatographic separation of cis-(±)-6 afforded inactive ent-6_P1 and active ent-6_P2. Compound 5 (P-gp ER = 0.9) and ent-6_P2 (P-gp ER = 1.1) demonstrated good Caco-2 permeability and are not actively effluxed by ABC transporters. In vitro analysis in HEK293T cells found that 5, cis-(±)-6, and ent-6_P2 showed near complete inhibition of PARP1 activity at 10 μM. Furthermore, compounds 5, cis-(±)-6, and ent-6_P2 displayed selective cytotoxic activity in BRCA mutant cancer cells but not isogenic BRCA-proficient cells. Taken together, 5 and ent-6_P2 define a novel class of lead PARP inhibitors for further development.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"776-783"},"PeriodicalIF":3.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950696","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

Structure-Activity Relationship Analysis of 2-Aryl-8-alkynyl Adenine and Nucleoside Scaffolds as A₃ Adenosine Receptor Ligands. 2-芳基-8-炔基腺嘌呤与核苷支架作为A3腺苷受体配体的构效关系分析。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-02 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00138

Gibae Kim, Grim Lee, Dnyandev B Jarhad, Zhan-Guo Gao, Seung Woo Kim, Misuk Joung, Kenneth A Jacobson, Lak Shin Jeong

{"title":"Structure-Activity Relationship Analysis of 2-Aryl-8-alkynyl Adenine and Nucleoside Scaffolds as A3 Adenosine Receptor Ligands.","authors":"Gibae Kim, Grim Lee, Dnyandev B Jarhad, Zhan-Guo Gao, Seung Woo Kim, Misuk Joung, Kenneth A Jacobson, Lak Shin Jeong","doi":"10.1021/acsmedchemlett.5c00138","DOIUrl":"10.1021/acsmedchemlett.5c00138","url":null,"abstract":"Numerous adenosine receptor (AR) ligands have been synthesized over many years, but the development of 2,8-disubstituted nucleoside derivatives was limited due to the lack of efficient synthetic methods. Leveraging Pd catalyst-controlled regioselective coupling, we embarked on structure-activity relationship (SAR) analyses at the C8 position. Our SAR studies revealed that an aliphatic alkyne chain of specific length, such as 1-hexyne, at the C8 position is ideally suited for hA2AAR interaction. A computational docking study revealed that the π-π interaction between His953.37 and C8-aromatic alkyne could induce an active conformation of hA3AR. Notably, compound 7b demonstrated exceptional potency and selectivity at hA3AR (K i,hA3 = 3.0 ± 0.5 nM), acting as the first 2,8-disubstituted nucleoside A3AR partial agonist. It underscores the strategic importance of C8 position modifications in modulating AR activity and function, paving the way for novel therapeutic agents targeting AR-mediated diseases.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"880-886"},"PeriodicalIF":3.5,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953487","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 Pyrido[3,4-d]pyrimidin-4-one and Pyrimido[5,4-d]pyrimidin-4-one Derivatives as TREM2 Agonists for Treating Parkinson’s Disease 新型吡啶[3,4-d]嘧啶-4- 1和吡啶[5,4-d]嘧啶-4- 1衍生物作为TREM2激动剂治疗帕金森病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-02 DOI: 10.1021/acsmedchemlett.5c0014510.1021/acsmedchemlett.5c00145

Ram W. Sabnis*,

引用次数: 0