Journal of Medicinal Chemistry最新文献_第3页

Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors. 钯介导的生物正交系统，用于原药激活含 N-苄基苯甲酰胺的管蛋白聚合抑制剂以治疗实体瘤。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-14 Epub Date: 2024-11-01 DOI: 10.1021/acs.jmedchem.4c02419

Jinlong Li, Tong Zhang, Di Wu, Chen He, Haoxiang Weng, Tiandong Zheng, Jie Liu, Hong Yao, Jichao Chen, Yansong Ren, Zheying Zhu, Jinyi Xu, Shengtao Xu

{"title":"Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors.","authors":"Jinlong Li, Tong Zhang, Di Wu, Chen He, Haoxiang Weng, Tiandong Zheng, Jie Liu, Hong Yao, Jichao Chen, Yansong Ren, Zheying Zhu, Jinyi Xu, Shengtao Xu","doi":"10.1021/acs.jmedchem.4c02419","DOIUrl":"10.1021/acs.jmedchem.4c02419","url":null,"abstract":"Bioorthogonal cleavage reactions have been developed as an intriguing strategy to enhance the safety of chemotherapeutics. Aiming to reduce the toxicity and improve the targeted release properties of the colchicine binding site inhibitors (CBSIs) based on previous work, a series of biologically inert prodrugs were further designed and synthesized through a bioorthogonal prodrug strategy. The therapeutic effects of prodrugs could be \"turned-on\" once combined with palladium resins. Particularly, prodrug 2b was 68.3-fold less cytotoxic compared to the parent compound, while its cytotoxicity was recovered in situ in the presence of palladium resins. Mechanism studies confirmed that 2b inhibited cell growth in the same manner as CBSIs. More importantly, in vivo efficacy studies demonstrated the efficient activation of 2b by palladium resins, resulting in significant inhibition of tumor growth (63.2%). These results suggest that prodrug 2b with improved safety and targeted release property catalyzed by a Pd-mediated bioorthogonal cleavage reaction deserves further investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556627","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 : 2024-11-14 Epub Date: 2024-11-04 DOI: 10.1021/acs.jmedchem.4c01752

Jinbiao Liao, Jianing Liao, Minkui Zhang, Yanzhen Yu, Lvtao Cai, Kaixin Le, Weitao Fu, Yiyang Qin, Tingjun Hou, Dan Li, 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, Rong Sheng","doi":"10.1021/acs.jmedchem.4c01752","DOIUrl":"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":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566388","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 : 2024-11-14 Epub Date: 2024-11-05 DOI: 10.1021/acs.jmedchem.4c01042

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

引用次数: 0

Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis 用于银屑病局部治疗的新型选择性 PDE4 抑制剂的设计、合成和生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI: 10.1021/acs.jmedchem.4c01804

Dengqin He, Gang Li, Jia-Qiang Wu, Yan Geng, Xudong Qian, Yuanhui Liu, Yanghui Ou, Mengjie Li, Jun Wang, Wei Pan, Guoping Zhang, Dandan Chen, Jiaxin Chen, Zichen Xu, Hengming Ke, Hongliang Yao

引用次数: 0

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation 新型二氨基嘧啶大环作为第四代可逆表皮生长因子受体（EGFR）抑制剂的设计、合成和生物学评价，可克服 C797S 突变介导的奥希替尼临床耐药性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI: 10.1021/acs.jmedchem.4c01975

Shiliang Hu, Linjiang Tong, Qiao Qin, Jiaxin Wen, Yan Li, Fang Feng, Kunzhong Wu, Yang Zhou, Jinsai Shang, Junjian Wang, Jinbao Liu, Hua Xie, Xiaoyun Lu

{"title":"Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation","authors":"Shiliang Hu, Linjiang Tong, Qiao Qin, Jiaxin Wen, Yan Li, Fang Feng, Kunzhong Wu, Yang Zhou, Jinsai Shang, Junjian Wang, Jinbao Liu, Hua Xie, Xiaoyun Lu","doi":"10.1021/acs.jmedchem.4c01975","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01975","url":null,"abstract":"Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFRT790M/C797S mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFRT790M/C797S inhibitors. The representative compound 21v potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 2.3 nM and 12.5 nM, respectively, and exhibited antiproliferative activity against Ba/F3-EGFR19del/T790M/C797S and Ba/F3-EGFRL858R/T790M/C797S cells with IC50 values of 41 and 52 nM, respectively. Further, 21v inhibited proliferation of the EGFR19del/T790M/C797S mutant PC-9-OR NSCLC cell line with an IC50 value of 56 nM and displayed selectivity over parental Ba/F3 and A431 cells. Moreover, 21v exhibited antitumor efficacy in a Ba/F3-EGFR19del/T790M/C797S xenograft model. This study provides a promising macrocyclic lead for anticancer drug discovery overcoming EGFRC797S mutation mediated resistance in NSCLC patients.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609863","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

Proline Analogues in Drug Design: Current Trends and Future Prospects 药物设计中的脯氨酸类似物：当前趋势与未来展望

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-12 DOI: 10.1021/acs.jmedchem.4c01987

Vladimir Kubyshkin, Pavel K. Mykhailiuk

引用次数: 0

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia 将 11-19 种白血病抑制剂列为急性髓性白血病口服候选药物的优先顺序

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-12 DOI: 10.1021/acs.jmedchem.4c01337

Xuejiao Shirley Guo, Sandeep Atla, Satyanarayana Nyalata, Yugendar R. Alugubelli, Peng-Hsun Chase Chen, Shiqing Xu, Wenshe Ray Liu

{"title":"Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia","authors":"Xuejiao Shirley Guo, Sandeep Atla, Satyanarayana Nyalata, Yugendar R. Alugubelli, Peng-Hsun Chase Chen, Shiqing Xu, Wenshe Ray Liu","doi":"10.1021/acs.jmedchem.4c01337","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01337","url":null,"abstract":"Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599573","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

Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics 用芳基氟硫酸盐共价靶向组氨酸残基：应用于 Mcl-1 BH3 拟态化合物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-12 DOI: 10.1021/acs.jmedchem.4c01541

Giulia Alboreggia, Parima Udompholkul, Emma L. Atienza, Kendall Muzzarelli, Zahra Assar, Maurizio Pellecchia

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Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists 以血管紧张素 II 受体为靶标的荧光配体的合成和药理特征，这些荧光配体来自于激动剂、β-阿司匹林类激动剂和拮抗剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-11 DOI: 10.1021/acs.jmedchem.4c01693

Céline Delaitre, Michel Boisbrun, Samir Acherar, André Dias, Alexandra Kleinclauss, Mathilde Achard, Mélissa Colin, Trung Minh Nguyen, Nicolas Humbert, Khawla Chmeis, Karen L. Martinez, Nicolas Gilles, Philippe Robin, Sandra Lecat, François Dupuis

{"title":"Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists","authors":"Céline Delaitre, Michel Boisbrun, Samir Acherar, André Dias, Alexandra Kleinclauss, Mathilde Achard, Mélissa Colin, Trung Minh Nguyen, Nicolas Humbert, Khawla Chmeis, Karen L. Martinez, Nicolas Gilles, Philippe Robin, Sandra Lecat, François Dupuis","doi":"10.1021/acs.jmedchem.4c01693","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01693","url":null,"abstract":"Angiotensin II (AngII) regulates cerebral circulation and binds with a similar affinity to AT1 and AT2 receptors. Biased AT1 agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the Gq pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT1 agonists on cells or tissues, such as the cerebral vessels. We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT1 antagonist losartan. We conducted pharmacological characterization to determine their selectivity, potency, and ability to activate or not specific AT1 transduction pathways in cells and cerebral arteries. We report the first highly AT1-selective fluorescent ligand, based on losartan, that retains its antagonist activity with high affinity. Fluorescent derivatives of TRV027 become AT2-selective and lose their AT1 β-arrestin bias. These new ligands can be applied to trace AT1 or AT2 receptors in vitro and ex vivo.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599040","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

Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery 非天然氨基酸：药物化学和药物发现中的策略、设计和应用

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-11 DOI: 10.1021/acs.jmedchem.4c00110

Krishna K. Sharma, Komal Sharma, Kamya Rao, Anku Sharma, Gajanan K. Rathod, Shams Aaghaz, Naina Sehra, Rajesh Parmar, Brett VanVeller, Rahul Jain

{"title":"Unnatural Amino Acids: Strategies, Designs, and Applications in Medicinal Chemistry and Drug Discovery","authors":"Krishna K. Sharma, Komal Sharma, Kamya Rao, Anku Sharma, Gajanan K. Rathod, Shams Aaghaz, Naina Sehra, Rajesh Parmar, Brett VanVeller, Rahul Jain","doi":"10.1021/acs.jmedchem.4c00110","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00110","url":null,"abstract":"Peptides can operate as therapeutic agents that sit within a privileged space between small molecules and larger biologics. Despite examples of their potential to regulate receptors and modulate disease pathways, the development of peptides with drug-like properties remains a challenge. In the quest to optimize physicochemical parameters and improve target selectivity, unnatural amino acids (UAAs) have emerged as critical tools in peptide- and peptidomimetic-based drugs. The utility of UAAs is illustrated by clinically approved drugs such as methyldopa, baclofen, and gabapentin in addition to small drug molecules, for example, bortezomib and sitagliptin. In this Perspective, we outline the strategy and deployment of UAAs in FDA-approved drugs and their targets. We further describe the modulation of the physicochemical properties in peptides using UAAs. Finally, we elucidate how these improved pharmacological parameters and the role played by UAAs impact the progress of analogs in preclinical stages with an emphasis on the role played by UAAs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599039","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