Journal of Medicinal Chemistry最新文献_第2页

Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis 发现 1-(苯磺酰基)-1,2,3,4-四氢喹啉衍生物可作为口服生物利用且安全的 RORγt 反向激动剂用于类风湿性关节炎的潜在治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI: 10.1021/acs.jmedchem.4c01727

Shan-Liang Sun, Hong-Jiang Xu, Xiao-Long Jiang, Jian Zhou, Wei Shi, Xiao-Jin Wang, Wei Song, Xia-Yun Chang, Xue-Qin Ma, Xiao-Fang Zou, Shi-Han Wu, Jin Yang, Qing-Qing Li, Zi-Xuan Wang, Jiao Cai, Shao-Peng Yu, Qing-Xin Wang, Tian-Hua Wei, Jia-Zhen Wu, Zhen-Jiang Tong, Yun Zhou, Yi-Bo Wang, Yan-Cheng Yu, Xue-Jiao Leng, Ning Ding, Zhi-Hao Shi, Wei-Chen Dai, Xin Xue, Nian-Guang Li, Xiao-Long Wang

{"title":"Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis","authors":"Shan-Liang Sun, Hong-Jiang Xu, Xiao-Long Jiang, Jian Zhou, Wei Shi, Xiao-Jin Wang, Wei Song, Xia-Yun Chang, Xue-Qin Ma, Xiao-Fang Zou, Shi-Han Wu, Jin Yang, Qing-Qing Li, Zi-Xuan Wang, Jiao Cai, Shao-Peng Yu, Qing-Xin Wang, Tian-Hua Wei, Jia-Zhen Wu, Zhen-Jiang Tong, Yun Zhou, Yi-Bo Wang, Yan-Cheng Yu, Xue-Jiao Leng, Ning Ding, Zhi-Hao Shi, Wei-Chen Dai, Xin Xue, Nian-Guang Li, Xiao-Long Wang","doi":"10.1021/acs.jmedchem.4c01727","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01727","url":null,"abstract":"The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it a significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which, D4 exhibited superior bioavailability (F = 48.1 and 32.9% in mice and rats, respectively) compared to GSK2981278 (F = 6.2 and 4.1%, respectively), and effectively treated psoriasis in mice at lower doses. Moreover, for the first time, we report the efficacies of a RORγt inverse agonist in mouse models of rheumatoid arthritis. (R)-D4, the eutomer of D4, matched or exceeded GSK2981278’s therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position (R)-D4 as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"58 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease. 发现并优化用于胎儿血红蛋白诱导治疗镰状细胞病的 WIZ 转录因子第一类分子胶降解剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-14 DOI: 10.1021/acs.jmedchem.4c02251

John Ryan Kerrigan, Noel M Thomsen, Artiom Cernijenko, Sarah E Kochanek, Janetta Dewhurst, Gary O'Brien, Nathaniel F Ware, Carina C Sanchez, James R Manning, Xiaolei Ma, Elizabeth Ornelas, Nikolas A Savage, James R Partridge, Andrew W Patterson, Philip Lam, Natalie A Dales, Simone Bonazzi, Sneha Borikar, Amelia E Hinman, Pamela Y Ting

{"title":"Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.","authors":"John Ryan Kerrigan, Noel M Thomsen, Artiom Cernijenko, Sarah E Kochanek, Janetta Dewhurst, Gary O'Brien, Nathaniel F Ware, Carina C Sanchez, James R Manning, Xiaolei Ma, Elizabeth Ornelas, Nikolas A Savage, James R Partridge, Andrew W Patterson, Philip Lam, Natalie A Dales, Simone Bonazzi, Sneha Borikar, Amelia E Hinman, Pamela Y Ting","doi":"10.1021/acs.jmedchem.4c02251","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02251","url":null,"abstract":"Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution. 一种强效选择性糜蛋白酶抑制剂 Fulacimstat（BAY 1142524）的发现和临床前表征，它是一种安全溶解血栓的新型纤溶方法。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-14 DOI: 10.1021/acs.jmedchem.4c01819

Chantal Fürstner, Jens Ackerstaff, Heinrich Meier, Alexander Straub, Joachim Mittendorf, Jens Schamberger, Martina Schäfer, Kirsten Börngen, Hannah Jörißen, Dmitry Zubov, Katja Zimmermann, Adrian Tersteegen, Volker Geiss, Elke Hartmann, Barbara Albrecht-Küpper, Pedro D'Orléans-Juste, Catherine Lapointe, Laurence Vincent, Stefan Heitmeier, Hanna Tinel

{"title":"Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution.","authors":"Chantal Fürstner, Jens Ackerstaff, Heinrich Meier, Alexander Straub, Joachim Mittendorf, Jens Schamberger, Martina Schäfer, Kirsten Börngen, Hannah Jörißen, Dmitry Zubov, Katja Zimmermann, Adrian Tersteegen, Volker Geiss, Elke Hartmann, Barbara Albrecht-Küpper, Pedro D'Orléans-Juste, Catherine Lapointe, Laurence Vincent, Stefan Heitmeier, Hanna Tinel","doi":"10.1021/acs.jmedchem.4c01819","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01819","url":null,"abstract":"Chymase is a serine-protease produced by mast cells. In the past few decades, its role in fibrotic diseases triggered the search for orally available chymase inhibitors. Aiming at reducing adverse cardiac remodeling after myocardial infarction, our research efforts resulted in the discovery of fulacimstat (BAY 1142524). While clinical trials did not demonstrate efficacy in this indication, the recent discovery of a new unexpected biological role of chymase spurred a revival of interest in chymase inhibition: chymase was shown to inactivate plasmin within fibrin-rich clots. Chymase inhibitors are now considered as potential profibrinolytic drugs with low bleeding risk and therefore exceptional safety for the treatment of acute thrombosis settings such as stroke, pulmonary embolism, or venous thrombosis. This article describes the chemical optimization journey from a screening hit to the discovery of fulacimstat (BAY 1142524), a selective chymase inhibitor with a good safety profile, as well as its preclinical in vitro and in vivo characterization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL) 发现微管相关丝氨酸/苏氨酸激酶样 (MASTL) 的高选择性抑制剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1021/acs.jmedchem.4c0165910.1021/acs.jmedchem.4c01659

Rebecca A. Gallego*, Stephanie Scales, Chad Toledo, Marin Auth, Louise Bernier, Madeline Berry, Sonja Brun, Loanne Chung, Carl Davis, Wade Diehl, Klaus Dress, Koleen Eisele, Jeff Elleraas, Jason Ewanicki, Yvette Fobian, Samantha Greasley, Eric C. Greenwald, Ted W. Johnson, Penney Khamphavong, Jennifer Lafontaine, Jian Li, Angelica Linton, Michael Maestre, Nichol Miller, Anwar Murtaza, Ryan L. Patman, Casey L. Quinlan, Dana J. Ramms, Paul Richardson, Neal Sach, Romelia Salomon-Ferrer, Francisco Silva, Sergei Timofeevski, Phuong Tran, Michelle Tran-Dubé, Fen Wang, Wei Wang, Martin Wythes, Shouliang Yang, Aihua Zou, Todd VanArsdale and Indrawan McAlpine*,

{"title":"Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)","authors":"Rebecca A. Gallego*, Stephanie Scales, Chad Toledo, Marin Auth, Louise Bernier, Madeline Berry, Sonja Brun, Loanne Chung, Carl Davis, Wade Diehl, Klaus Dress, Koleen Eisele, Jeff Elleraas, Jason Ewanicki, Yvette Fobian, Samantha Greasley, Eric C. Greenwald, Ted W. Johnson, Penney Khamphavong, Jennifer Lafontaine, Jian Li, Angelica Linton, Michael Maestre, Nichol Miller, Anwar Murtaza, Ryan L. Patman, Casey L. Quinlan, Dana J. Ramms, Paul Richardson, Neal Sach, Romelia Salomon-Ferrer, Francisco Silva, Sergei Timofeevski, Phuong Tran, Michelle Tran-Dubé, Fen Wang, Wei Wang, Martin Wythes, Shouliang Yang, Aihua Zou, Todd VanArsdale and Indrawan McAlpine*, ","doi":"10.1021/acs.jmedchem.4c0165910.1021/acs.jmedchem.4c01659","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01659https://doi.org/10.1021/acs.jmedchem.4c01659","url":null,"abstract":"By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19234–19246 19234–19246"},"PeriodicalIF":6.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Medicinal Chemistry Education and Training 药物化学教育与培训

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1021/acs.jmedchem.4c0261910.1021/acs.jmedchem.4c02619

Craig W. Lindsley*,

引用次数: 0

Target Ligand Separation and Identification of Isoforsythiaside as a Histone Lysine-Specific Demethylase 1 Covalent Inhibitor Against Breast Cancer Metastasis 目标配体分离与异佛手苷作为组蛋白赖氨酸特异性去甲基化酶 1 共价抑制剂抗乳腺癌转移的鉴定

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1021/acs.jmedchem.4c0227710.1021/acs.jmedchem.4c02277

Mengzhen Gu, Xiaoqing Xu, Xiaoping Wang, Yun Wang, Yu Zhao, Xiaoxian Hu, Lu Zhu*, Zhenzhong Deng* and Chao Han*,

{"title":"Target Ligand Separation and Identification of Isoforsythiaside as a Histone Lysine-Specific Demethylase 1 Covalent Inhibitor Against Breast Cancer Metastasis","authors":"Mengzhen Gu, Xiaoqing Xu, Xiaoping Wang, Yun Wang, Yu Zhao, Xiaoxian Hu, Lu Zhu*, Zhenzhong Deng* and Chao Han*, ","doi":"10.1021/acs.jmedchem.4c0227710.1021/acs.jmedchem.4c02277","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02277https://doi.org/10.1021/acs.jmedchem.4c02277","url":null,"abstract":"Histone lysine-specific demethylase 1 (LSD1) is hyperactive in breast cancer, which is associated with the metastasis of the tumor. Current irreversible LSD1 inhibitors are all synthesized by covalently binding to the flavin adenine dinucleotide cofactor, which often have side effects due to the high affinity for a variety of targets. Here, we identified isoforsythiaside (IFA), a natural phenylpropanoid glycoside isolated from Forsythia suspensa, as a novel covalent inhibitor of LSD1. The target ligand fishing technique and LC–MS/MS analysis identified that IFA could covalently bind to the Ser817 residue of LSD1 by α,β-unsaturated ketone moiety to block the amine oxidase-like domain of LSD1. Moreover, RBMS3/Twist1/MMP2, the downstream signaling pathway of LSD1, was activated after IFA treatment to inhibit the metastasis of MDA-MB-231 cells in vitro and in vivo. This study provided novel molecular templates for development of LSD1 covalence-binding inhibitor and laid a foundation for developing agents against breast carcinoma metastasis for targeting LSD1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19874–19888 19874–19888"},"PeriodicalIF":6.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Inhibition of Human Salivary and Pancreatic α-Amylase by Resveratrol Oligomers 白藜芦醇低聚物对人类唾液和胰腺α-淀粉酶的抑制作用

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1021/acs.jmedchem.4c0104210.1021/acs.jmedchem.4c01042

Rizliya Visvanathan, Dang Truong Le, Sushil Dhital, Topul Rali, Rohan A. Davis and Gary Williamson*,

{"title":"Inhibition of Human Salivary and Pancreatic α-Amylase by Resveratrol Oligomers","authors":"Rizliya Visvanathan, Dang Truong Le, Sushil Dhital, Topul Rali, Rohan A. Davis and Gary Williamson*, ","doi":"10.1021/acs.jmedchem.4c0104210.1021/acs.jmedchem.4c01042","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01042https://doi.org/10.1021/acs.jmedchem.4c01042","url":null,"abstract":"A key strategy to mitigate postprandial hyperglycemia involves inhibiting α-amylases, which commence the starch digestion process in the gut. This study examined the inhibitory effects of resveratrol and stilbenoid tetramers, vaticanol B, (−)-hopeaphenol, and vatalbinoside A on human salivary and pancreatic α-amylases experimentally and through molecular docking studies. Vaticanol B demonstrated the most potent inhibition with IC50 values of 5.3 ± 0.3 μM for salivary and 6.1 ± 0.5 μM for pancreatic α-amylase (compared to acarbose with IC50 values of 1.2 ± 0.1 μM and 0.5 ± 0.0 μM, respectively). Kinetic analysis suggested a competitive inhibition mode for vaticanol B. Resveratrol and vatalbinoside A were poor inhibitors of human α-amylases, while (−)-hopeaphenol exhibited moderate inhibition. Molecular docking supported the inhibition data, and several aspects of the structural configurations explained the stronger inhibition exerted by vaticanol B. Overall, vaticanol B shows promise as a natural alternative to acarbose for inhibiting α-amylase.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"18753–18763 18753–18763"},"PeriodicalIF":6.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c01042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Expanding the Solvent/Protein Region Occupation of the Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket for Improved Broad-Spectrum Anti-HIV-1 Efficacy: from Rigid Phenyl-Diarylpyrimidines to Flexible Hydrophilic Piperidine-Diarylpyrimidines 扩大非核苷类逆转录酶抑制剂结合口袋的溶剂/蛋白质区域占位以提高广谱抗 HIV-1 效能：从刚性苯基-二芳基嘧啶到柔性亲水性哌啶-二芳基嘧啶

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI: 10.1021/acs.jmedchem.4c0241310.1021/acs.jmedchem.4c02413

Wen-Juan Huang, Christophe Pannecouque, Erik De Clercq, Angela Corona, Stefania Maloccu, Enzo Tramontano, Shuai Wang* and Fen-Er Chen*,

{"title":"Expanding the Solvent/Protein Region Occupation of the Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket for Improved Broad-Spectrum Anti-HIV-1 Efficacy: from Rigid Phenyl-Diarylpyrimidines to Flexible Hydrophilic Piperidine-Diarylpyrimidines","authors":"Wen-Juan Huang, Christophe Pannecouque, Erik De Clercq, Angela Corona, Stefania Maloccu, Enzo Tramontano, Shuai Wang* and Fen-Er Chen*, ","doi":"10.1021/acs.jmedchem.4c0241310.1021/acs.jmedchem.4c02413","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02413https://doi.org/10.1021/acs.jmedchem.4c02413","url":null,"abstract":"Considering the nonideal antiresistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor 7, a series of novel piperidine-diarylpyrimidine derivatives were designed through expanding solvent/protein region occupation. The representative compound 15f proved to be exceptionally potent against Y188L (EC50 = 23 nM), F227L + V106A (EC50 = 15 nM) and RES056 (EC50 = 45 nM), significantly better than 7. This analog exerted strong inhibition against wild-type HIV-1 (EC50 = 3 nM) and single mutant strains (L100I, K103N, Y181C, E138 K). Notably, its cytotoxicity and selectivity (CC50 = 18.23 μM, SI = 6537) were 4-fold better than etravirine and rilpivirine. Additionally, it exhibited minimal suppression of CYP isoenzymes and hERG, indicating low potential for drug–drug interactions and cardiotoxicity. No significant acute toxicity and tissue damage at a dose of 2 g/kg were revealed. These findings lay the groundwork for the advancement of 15f as a highly potent, safe, and broad-spectrum NNRTI for HIV therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19889–19904 19889–19904"},"PeriodicalIF":6.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer 鉴定可口服生物利用的香豆素衍生物作为针对前列腺癌的潜在 AR 拮抗剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-04 DOI: 10.1021/acs.jmedchem.4c0175210.1021/acs.jmedchem.4c01752

Jinbiao Liao, Jianing Liao, Minkui Zhang, Yanzhen Yu, Lvtao Cai, Kaixin Le, Weitao Fu, Yiyang Qin, Tingjun Hou, Dan Li* and Rong Sheng*,

{"title":"Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer","authors":"Jinbiao Liao, Jianing Liao, Minkui Zhang, Yanzhen Yu, Lvtao Cai, Kaixin Le, Weitao Fu, Yiyang Qin, Tingjun Hou, Dan Li* and Rong Sheng*, ","doi":"10.1021/acs.jmedchem.4c0175210.1021/acs.jmedchem.4c01752","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01752https://doi.org/10.1021/acs.jmedchem.4c01752","url":null,"abstract":"Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19395–19416 19395–19416"},"PeriodicalIF":6.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Optimization of Antiproliferative Properties of Triimine Copper(II) Complexes 优化三亚胺铜(II)配合物的抗增殖特性

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-04 DOI: 10.1021/acs.jmedchem.4c0180610.1021/acs.jmedchem.4c01806

Katarzyna Choroba, Bartosz Zowiślok, Sławomir Kula, Barbara Machura, Anna M. Maroń*, Karol Erfurt, Cristiana Marques, Sandra Cordeiro, Pedro V. Baptista and Alexandra R. Fernandes*,

{"title":"Optimization of Antiproliferative Properties of Triimine Copper(II) Complexes","authors":"Katarzyna Choroba, Bartosz Zowiślok, Sławomir Kula, Barbara Machura, Anna M. Maroń*, Karol Erfurt, Cristiana Marques, Sandra Cordeiro, Pedro V. Baptista and Alexandra R. Fernandes*, ","doi":"10.1021/acs.jmedchem.4c0180610.1021/acs.jmedchem.4c01806","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01806https://doi.org/10.1021/acs.jmedchem.4c01806","url":null,"abstract":"Cu(II) complexes with 2,2′:6′,2″-terpyridines (terpy) and 2,6-bis(thiazol-2-yl)pyridines (dtpy) with 1- or 2-naphtyl and methoxy-naphtyl were synthesized to elucidate the impact of the triimine core, naphtyl linking mode, and presence of methoxy groups on the antiproliferative activity of [CuCl2(Ln)]. Their antiproliferative effect was analyzed in ovarian (A2780) and colorectal (HCT116) carcinomas and colorectal carcinoma resistant to doxorubicin (HCT116-DoxR) cell lines and in normal human fibroblasts. Among all complexes, the 1- and 2-naphtyl substituted terpy Cu(II) complexes (Cu1a and Cu1b) showed the strongest cytotoxicity, namely, in HCT116-DoxR 2Dcells and were also capable of inducing the loss of cell viability in 3D HCT116-DoxR spheroids. Their intracellular localization, capability to increase reactive oxygen species (ROS), and interaction with DNA (nonintercalative mode) trigger oxidative DNA cleavage leading to cell death by apoptosis and autophagy. Cu1a and Cu1b do not show in vivo toxicity in a chicken embryo and can interact with bovine serum albumin (BSA).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 21","pages":"19475–19502 19475–19502"},"PeriodicalIF":6.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c01806","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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