ChemMedChem最新文献_第6页

Front Cover: [18F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System (ChemMedChem 4/2025) [18F]NP3-627，一种靶向中枢神经系统NLRP3炎性体的PET显像剂（ChemMedChem 4/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-17 DOI: 10.1002/cmdc.202580401

Dr. David M. Whitehead, Dr. Christian Fischer, Dr. Emmanuelle Briard, Dr. Christopher J. Farady, Nadège Graveleau, Joel Karrer, Dr. Klemens Kaupmann, Dr. Guillaume Lapointe, Dr. Angela Mackay, Lisa Reichert, Michael Wright, Dr. Linjing Mu, Dr. Yves P. Auberson

{"title":"Front Cover: [18F]NP3-627, a Candidate PET Imaging Agent Targeting the NLRP3 Inflammasome in the Central Nervous System (ChemMedChem 4/2025)","authors":"Dr. David M. Whitehead, Dr. Christian Fischer, Dr. Emmanuelle Briard, Dr. Christopher J. Farady, Nadège Graveleau, Joel Karrer, Dr. Klemens Kaupmann, Dr. Guillaume Lapointe, Dr. Angela Mackay, Lisa Reichert, Michael Wright, Dr. Linjing Mu, Dr. Yves P. Auberson","doi":"10.1002/cmdc.202580401","DOIUrl":"https://doi.org/10.1002/cmdc.202580401","url":null,"abstract":"The image shows the structure of the positron emission tomography (PET) imaging agent [18F]NP3-627, which can penetrate the brain and bind to the NACHT domain of NLRP3. In the background, we see the structure of the NLRP3 inflammasome complex, whose increased expression in inflammatory conditions offers the potential for [18F]NP3-627 to quantify inflammation in e.g., Alzheimer's disease, multiple sclerosis, or associated with other causes of neurodegeneration. Such a biomarker will facilitate the development of anti-inflammatory drugs acting on the NLRP3 inflammasome, as novel treatments for these conditions. More details can be found in article 10.1002/cmdc.202400816 by Yves P. Auberson and co-workers.<figure>\u0000 <div><picture>\u0000 <source></source></picture>\u0000 </div>\u0000 </figure>\u0000 ","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 4","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202580401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Cover Feature: Design, Synthesis, and Anti-Prostate Cancer Potential of 2-(4-Nitrobenzyl) Malonates In Vitro and DAL Acute Oral Toxicity Assessment In Vivo (ChemMedChem 4/2025) 封面专题：2-（4-硝基苯）丙二酸盐的设计、合成、体外抗前列腺癌潜力和DAL急性口服体内毒性评估（ChemMedChem 4/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-17 DOI: 10.1002/cmdc.202580402

Bharathi Hassan Ganesh, Baladhandapani Aruchamy, Srikrishna Mudradi, Sarthak Mohanty, Himabindu Padinjarathil, Simone Carradori, Prasanna Ramani

引用次数: 0

Fast Release of Carboxylic Acid inside Cells. 细胞内羧酸的快速释放。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-17 DOI: 10.1002/cmdc.202500056

Pascal Moser, Renaud Zelli, Leandro J Dos Santos, Mickaël Henry, Kevin Sanchez-Garcia, Yvan Caspar, Florian C Marro, Benoit Chovelon, Jaione Saez Cabodevilla, Sandrine Ollagnier de Choudens, Eric Faudry, Yung-Sing Wong

{"title":"Fast Release of Carboxylic Acid inside Cells.","authors":"Pascal Moser, Renaud Zelli, Leandro J Dos Santos, Mickaël Henry, Kevin Sanchez-Garcia, Yvan Caspar, Florian C Marro, Benoit Chovelon, Jaione Saez Cabodevilla, Sandrine Ollagnier de Choudens, Eric Faudry, Yung-Sing Wong","doi":"10.1002/cmdc.202500056","DOIUrl":"https://doi.org/10.1002/cmdc.202500056","url":null,"abstract":"Delivering carboxylic acid functions into cells is challenging due to their poor permeability across lipophilic membranes at physiological pH, where they are ionized. Masking carboxylic acids as esters improves cell entry, but once inside the cell, its rapid release is essential to maintain spatiotemporal control which can be beneficial for therapeutic and diagnostic applications. This study evaluates the 2-hydroxyethyl-dithio-benzyl ester functional group which undergoes selective and rapid cleavage of the disulfide bond by thioredoxin (Trx), triggering rapid self-immolation of the thio-benzyl ester releasing the carboxylic acid. Fluorescence-based assays using the pro-fluorescent BODIPY structure have demonstrated the rapid intracellular release of carboxylic acids within minutes in both eukaryotic and prokaryotic cells. The approach was tested on antibiotics, and among them, levofloxacin ester prodrug, having the 2-hydroxyethyl-dithio-benzyl ester functional group, showed significantly enhanced antimicrobial activity against resistant and intracellular bacteria compared to its methyl ester analogue.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500056"},"PeriodicalIF":3.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Advances in Lipid Nanoparticle-Based Disease Treatment. 基于脂质纳米颗粒的疾病治疗进展。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-17 DOI: 10.1002/cmdc.202400938

Yujie Zhou, Qiqi Ge, Xin Wang, Yuhui Wang, Qianqian Sun, Jianhao Wang, Tie Yang, Cheng Wang

{"title":"Advances in Lipid Nanoparticle-Based Disease Treatment.","authors":"Yujie Zhou, Qiqi Ge, Xin Wang, Yuhui Wang, Qianqian Sun, Jianhao Wang, Tie Yang, Cheng Wang","doi":"10.1002/cmdc.202400938","DOIUrl":"https://doi.org/10.1002/cmdc.202400938","url":null,"abstract":"Lipid nanoparticles (LNPs) have emerged as a transformative platform for the targeted delivery of therapeutic agents, revolutionizing treatment paradigms across a spectrum of diseases. Since the inception of liposomes in the 1960s, lipid-based nanotechnology has evolved to address limitations such as poor bioavailability, off-target effects, and instability, thereby enhancing the efficacy and safety of drug administration. This review highlights the latest advancements in LNPs technology, focusing on their application in cancer therapy, gene therapy, infectious disease management, glaucoma, and other clinical areas. Recent studies underscore the potential of LNPs to deliver messenger RNA (mRNA) and small interfering RNA (siRNA) for precise genetic intervention, exemplified by breakthroughs in RNA interference and CRISPR-Cas9 genome editing. Additionally, LNPs have been successfully employed to ameliorate conditions, demonstrating their versatility in addressing both acute and chronic disorders. However, challenges persist concerning large-scale manufacturing, long-term stability, and comprehensive safety evaluations. Future research must focus on optimizing formulations, exploring synergistic combinations with existing therapies, and expanding the scope of treatable diseases. The integration of LNPs into personalized medicine and the exploration of applications in other diseases represent promising avenues for further investigation. LNPs are poised to play an increasingly central role in the development of next-generation therapeutics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400938"},"PeriodicalIF":3.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit to Lead 欧洲药物化学和化学生物学联合会（EFMC）最佳实践倡议：打到领先。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-16 DOI: 10.1002/cmdc.202400931

Jean Quancard, Anders Bach, Chiara Borsari, Russell Craft, Christian Gnamm, Stéphanie M. Guéret, Ingo V. Hartung, Hannes F. Koolman, Stefan Laufer, Susan Lepri, Josef Messinger, Kurt Ritter, Gianluca Sbardella, Andrea Unzue Lopez, Marina K. Willwacher, Brian Cox, Robert J. Young

{"title":"The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit to Lead","authors":"Jean Quancard, Anders Bach, Chiara Borsari, Russell Craft, Christian Gnamm, Stéphanie M. Guéret, Ingo V. Hartung, Hannes F. Koolman, Stefan Laufer, Susan Lepri, Josef Messinger, Kurt Ritter, Gianluca Sbardella, Andrea Unzue Lopez, Marina K. Willwacher, Brian Cox, Robert J. Young","doi":"10.1002/cmdc.202400931","DOIUrl":"10.1002/cmdc.202400931","url":null,"abstract":"The Hit to Lead (H2L) process is an integral part of contemporary drug discovery, encompassing the optimisation of validated Hit structures into Lead molecules. High quality leads build confidence, through activity and property profiles as well as preliminary biological data, which might include validating pharmacologic hypotheses along the way, indicating that further investment in the structure(s) and target would be worthwhile. Leads have line of sight to a development candidate and bring an understanding of what priorities Lead Optimisation should address. In this set of best practices, we detail the essential criteria that characterise a good lead, which include establishing SAR from analogues and assessing preliminary DMPK indicators, selectivity and early safety parameters. We highlight the importance of identifying liabilities of the lead series and demonstrating that each can be individually modulated whilst maintaining on target potency. We make the case for having physicochemical properties as critical optimisation parameters and how ligand efficiency metrics can enable this. Then we go over general tactics that can be used to convert hits into a lead series. These include essential steps that, when performed early, increase the chance of success such as deconstructive SAR, pharmacophore and bioactive conformation determination and scaffold optimisation. Finally, we suggest decision-making criteria to substantiate confidence in further investment or, as importantly, making a recommendation to cease further work on a series.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 8","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202400931","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

CORRIGENDUM: Synthesis of 1,2,3-Triazole-Methyl-Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood-Dwelling Parasites 更正：1,2,3-三唑-甲基甲萘醌衍生物的合成：对两种血栖寄生虫的电化学和抗寄生性能的评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-13 DOI: 10.1002/cmdc.202500043

引用次数: 0

Synthesis and Bio-Evaluation of Quaternized Fused-β-Carbolines as Anti-MRSA Agents. 季铵化融合β-碳胺抗mrsa药物的合成及生物评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-13 DOI: 10.1002/cmdc.202400955

Adilakshmi Vutla, Deepanshi Saxena, Rahul Maitra, Sidharth Chopra, Sanjay Batra

引用次数: 0

Analogues of Natural Macarangin B Display Potent Antiviral Activity and Better Metabolic Stability. 天然Macarangin B的类似物显示出有效的抗病毒活性和更好的代谢稳定性。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-12 DOI: 10.1002/cmdc.202400978

Gwenaëlle Jézéquel, Jules Fargier, Joëlle Bigay, Joël Polidori, Justine Geslin, Nathalie Hue, Chaker El Kalamouni, Sandy Desrat, Fanny Roussi

{"title":"Analogues of Natural Macarangin B Display Potent Antiviral Activity and Better Metabolic Stability.","authors":"Gwenaëlle Jézéquel, Jules Fargier, Joëlle Bigay, Joël Polidori, Justine Geslin, Nathalie Hue, Chaker El Kalamouni, Sandy Desrat, Fanny Roussi","doi":"10.1002/cmdc.202400978","DOIUrl":"10.1002/cmdc.202400978","url":null,"abstract":"The development of innovative antiviral strategies is critical to address the global health threats posed by RNA viruses, including the Zika virus (ZIKV), which can cause severe neurological complications. The lipid transporter Oxysterol Binding Protein (OSBP), essential for cholesterol and phosphatidylinositol 4-phosphate trafficking, is exploited by many positive-strand RNA viruses, making it an attractive novel antiviral target. This study investigates simplified analogues of macarangin B, a natural compound with potent OSBP-targeted antiviral activity against ZIKV, but limited stability due to its flavonol moiety. A series of analogues was synthesized, replacing the flavonol with a flavone core while retaining the essential hexahydroxanthene (HHX) motif. These compounds demonstrated improved stability (t1/2=16 hours), high OSBP binding affinity (4 - 69 nM), and low cytotoxicity (>20 μM). The most active compounds exhibited antiviral activity comparable to established OSBP inhibitors and were stable in physiologic media, highlighting their potential as leads for therapeutic development. This work advances the structure-activity relationship (SAR) understanding of macarangin B analogues and provides a foundation for designing effective antivirals targeting in ZIKV infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400978"},"PeriodicalIF":3.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

GDF15 Analogues Acting as GFRAL Ligands. GDF15类似物作为GFRAL配体。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-05 DOI: 10.1002/cmdc.202400961

Andrea Di Santo, Livio Tarchi, Gianluca Villa, Giovanni Castellini, Valdo Ricca, Roberta Squecco, Anna Maria Papini, Feliciana Real-Fernandez, Paolo Rovero

{"title":"GDF15 Analogues Acting as GFRAL Ligands.","authors":"Andrea Di Santo, Livio Tarchi, Gianluca Villa, Giovanni Castellini, Valdo Ricca, Roberta Squecco, Anna Maria Papini, Feliciana Real-Fernandez, Paolo Rovero","doi":"10.1002/cmdc.202400961","DOIUrl":"10.1002/cmdc.202400961","url":null,"abstract":"Growth differentiation factor 15 (GDF15) is a TGF-β superfamily member involved in diverse physiological and pathological processes. It is expressed in various tissues and its circulating levels rise during exercise, aging, pregnancy, and conditions such as cancer, cardiovascular disease, and infections. The biological activities of GDF15, including anorexia and cachexia, are primarily mediated through the GFRAL receptor, localized in the brainstem and functioning via RET co-receptor recruitment. This signaling is crucial for energy homeostasis and nausea induction. Recent studies suggest a broader GFRAL distribution, potentially explaining GDF15's distinct roles. These findings sparked interest in leveraging GDF15-GFRAL pathways for therapeutic development. Two primary strategies include GDF15 analogues as GFRAL agonists for obesity treatment and GDF15-derived peptides as antagonists to counteract cancer-induced cachexia and related disorders. This review highlights advancements in understanding GDF15-GFRAL signaling and its implications, summarizing bioactive GDF15-derived molecules, their pharmacological applications, and offering insights into novel treatment avenues for GDF15-associated conditions.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400961"},"PeriodicalIF":3.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Design and Synthesis of ⁶⁸Ga-Labeled Peptide-Based Heterodimers for Dual Targeting of NTS₁ and GRPR. 基于68ga标记肽的异源二聚体的设计与合成，用于NTS1和GRPR的双重靶向。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-02-05 DOI: 10.1002/cmdc.202400843

Sacha Bodin, Santo Previti, Emmanuelle Jestin, Emmanuelle Rémond, Delphine Vimont, Frédéric Lamare, Imade Ait-Arsa, Elif Hindié, Florine Cavelier, Clément Morgat

{"title":"Design and Synthesis of 68Ga-Labeled Peptide-Based Heterodimers for Dual Targeting of NTS1 and GRPR.","authors":"Sacha Bodin, Santo Previti, Emmanuelle Jestin, Emmanuelle Rémond, Delphine Vimont, Frédéric Lamare, Imade Ait-Arsa, Elif Hindié, Florine Cavelier, Clément Morgat","doi":"10.1002/cmdc.202400843","DOIUrl":"10.1002/cmdc.202400843","url":null,"abstract":"Tumor heterogeneity remains one of the main obstacles for cancer diagnosis and treatment. The simultaneous targeting of several cancer biomarkers is an appealing approach for improved diagnostic procedures. Neurotensin receptor 1 (NTS1) and Gastrin-Releasing Peptide Receptor (GRPR) are both G-protein coupled receptors with complementary profile of expression in several cancer types. This work proposes the design, the synthesis and the in vitro radiopharmaceutical characterization of three heterodimers, based on GRP/NT modified peptides, radiolabeled with gallium-68. Two NTS1/GRPR targeting pharmacophores containing linear hybrids that differ in the C-terminus were synthesized (i. e., JMV 7110 and JMV 7253). The branched analogue of the silicon-containing heterodimer JMV 7110, namely JMV 7266, was also synthesized. After radiolabeling with 68Ga, saturation binding studies performed on HT29 (NTS1 +/GRPR-) and PC3 (NTS1 +/GRPR+) cells demonstrated a significant loss in NTS1 and GRPR affinity compared to the reference monomers with the exception of the NTS1 affinity of [68Ga]Ga-JMV 7266 which was preserved. Considering cellular processing, NTS1-internalization at 1 h was the highest with [68Ga]Ga-JMV 7266 and was similar to the reference compound. Interestingly [68Ga]Ga-JMV 7266 demonstrated lower efflux than the other linear heterodimers but also than its NT reference compound. The branched structure of [68Ga]Ga-JMV 7266 seems beneficial for dual NTS1/GRPR targeting.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400843"},"PeriodicalIF":3.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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