Journal of Medicinal Chemistry最新文献

New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-29 DOI: 10.1021/acs.jmedchem.4c03150

Federica Matteucci, Pegi Pavletić, Alessandro Bonifazi, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Consuelo Amantini, Laura Zeppa, Emanuela Sabato, Giulio Vistoli, Rian Garland, Hideaki Yano, Monica Castagna, Valerio Mammoli, Loredana Cappellacci, Alessia Piergentili, Wilma Quaglia

{"title":"New Arylpiperazines as Potent and Selective Dopamine D4 Receptor Ligands Potentially Useful to Treat Glioblastoma","authors":"Federica Matteucci, Pegi Pavletić, Alessandro Bonifazi, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Consuelo Amantini, Laura Zeppa, Emanuela Sabato, Giulio Vistoli, Rian Garland, Hideaki Yano, Monica Castagna, Valerio Mammoli, Loredana Cappellacci, Alessia Piergentili, Wilma Quaglia","doi":"10.1021/acs.jmedchem.4c03150","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03150","url":null,"abstract":"The dopamine D4 receptor (D4R) has recently been proposed as an emerging target for treating glioblastoma (GBM). In this article, new piperazine ligands, analogues of the potent and selective D4R lead compounds 9 and 10, were prepared and evaluated for their affinity at D2-like receptor subtypes. The most promising results were obtained by replacing the N4-phenyl terminal of 9 with a naphthyl group. Indeed, α-naphthyl derivative 15 proved to have four times higher affinity for D4R than lead 9, whereas β-naphthyl compound 16 was about tenfold more selective for D4R than 9. These compounds behaved as D4R antagonists in both Gi/Go activation and β-arrestin2 recruitment assays. Interestingly, both decreased cell viability dose-dependently and altered the cell cycle of U87 MG, T98G, and U251 MG human GBM cell lines after 48 h treatment, inducing an increase in ROS levels and time-dependent mitochondrial depolarization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734401","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

The Sprint to Develop Coronavirus Antivirals

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI: 10.1021/acs.jmedchem.5c00578

Michael F. T. Koehler

引用次数: 0

Design, Synthesis, Evaluation, and SAR of 5-Phenylisoindoline Derivatives, a Potent Class of Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) Interaction

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI: 10.1021/acs.jmedchem.4c02206

Tian Lu, Jiyi Zhang, Qiyu Chen, Mengyue Ni, Jingwen Zhang, Yufei Wu, Ruining Jia, Yuji Wang

{"title":"Design, Synthesis, Evaluation, and SAR of 5-Phenylisoindoline Derivatives, a Potent Class of Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) Interaction","authors":"Tian Lu, Jiyi Zhang, Qiyu Chen, Mengyue Ni, Jingwen Zhang, Yufei Wu, Ruining Jia, Yuji Wang","doi":"10.1021/acs.jmedchem.4c02206","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02206","url":null,"abstract":"A novel series of 5-phenylisoindoline derivatives were designed, synthesized, and evaluated for their activity to inhibit the interaction of PD-1/PD-L1 through the homogeneous time-resolved fluorescence assay. Meanwhile, structure-activity relationships were discussed according to both experiments and calculations. Several compounds exhibited potent activity with an IC50 value less than 10 nM, especially D6 (4.8 nM). D6 could promote IFN-γ secretion and reduce the proportion of PD-L1 late apoptosis at 100 nM in the coculture model of peripheral blood mononuclear cells and hPD-L1-FC. Beyond this, the in vitro model showed D6 could lead to the weakening of migration caused by the PD-1/PD-L1 axis. Furthermore, D6 also displayed dose-dependent and low-toxic efficacy in the MC38 mouse tumor model with the tumor growth inhibition of 52.8% (20 mg/kg, ip) and 64.4% (160 mg/kg, i.g.). Mechanistic investigations suggested that D6 could activate the immune microenvironment in the tumor. Thus, D6 is a promising small molecule lead for blocking PD-1/PD-L1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734352","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 the 2,3-Dihydrobenzopyrane-4-one as a Potent FTO Inhibitor against Obesity-Related Metabolic Diseases

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI: 10.1021/acs.jmedchem.4c03124

Duo Ma, Xianan Liu, Xingxing Zhang, Yaling Hong, Yumeng Wang, Famin Zhang, Leran Du, Junjie Zhao, Quan Wang, Cui Chang, Wenhu Liu, Yan Lou, Xinhua Liu

{"title":"Discovery of the 2,3-Dihydrobenzopyrane-4-one as a Potent FTO Inhibitor against Obesity-Related Metabolic Diseases","authors":"Duo Ma, Xianan Liu, Xingxing Zhang, Yaling Hong, Yumeng Wang, Famin Zhang, Leran Du, Junjie Zhao, Quan Wang, Cui Chang, Wenhu Liu, Yan Lou, Xinhua Liu","doi":"10.1021/acs.jmedchem.4c03124","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03124","url":null,"abstract":"The involvement of the fat mass and obesity-associated gene (FTO) in the development and advancement of metabolic disorders is widely recognized. However, the existing FTO inhibitor entacapone has been limited in clinical application due to its low potency and short plasma elimination half-life. Here, through drug library screening and in depth structure–activity relationship analysis, title compound 40, eriodictyol was identified as a potent FTO inhibitor, and showed good binding to FTO by surface plasmon resonance (SPR) and Microscale thermophoresis (MST) detection. The residues Arg96, Tyr108, Ser229, Asp233, and Glu234 of FTO are essential for binding. Meanwhile, eriodictyol attenuated obesity-related metabolic diseases by enhancing glucose metabolism pathways via the FTO-FOXO1-G6PC/PCK1 axis and increasing adipose tissue heat production for weight loss via the FTO-FOXO1-Ucp1 axis in vivo. Surprisingly, eriodictyol showed good pharmacokinetic properties and no obvious toxicity. These results could provide the reference for design of new FTO inhibitors against obesity-related metabolic diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"59 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723631","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

NIR-II aza-BODIPY Platform for the Development of a Fluorescent Antibody Drug Conjugate

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI: 10.1021/acs.jmedchem.4c02777

Elisa Chazeau, Angélique Pipier, K. David Wegner, François Ghiringhelli, Lucie Sancey, Catherine Paul, Christine Goze

{"title":"NIR-II aza-BODIPY Platform for the Development of a Fluorescent Antibody Drug Conjugate","authors":"Elisa Chazeau, Angélique Pipier, K. David Wegner, François Ghiringhelli, Lucie Sancey, Catherine Paul, Christine Goze","doi":"10.1021/acs.jmedchem.4c02777","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02777","url":null,"abstract":"Real-time imaging of antibody-drug conjugates (ADCs) offers valuable insights for assessing tumor targeting specificity, monitoring therapeutic efficacy, and detecting off-target accumulation that may cause adverse effects. To enable precise tracking, we developed a versatile fluorescent platform based on an NIR-II emitting aza-BODIPY dye, which can be site-specifically grafted onto an IgG1 antibody to generate well-defined fluorescent ADCs. As a proof of concept, we synthesized an HER2-targeting trastuzumab immunoconjugate bearing a NIR-II aza-BODIPY fluorophore. The cytotoxic monomethyl auristatin E (MMAE) payload was introduced in the final step, resulting in a trackable and homogeneous ADC suitable for both in vitro and in vivo investigations. The resulting Trastu-azaNIRII-MMAE selectively accumulated in HER2-positive subcutaneous tumors, significantly reducing the tumor growth. Using NIR-II optical imaging, a single injection of the NIR-II-ADC allowed for the detection of the conjugate over a period of more than one month, highlighting its potential for long-term tracking and therapeutic applications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"98 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723630","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

Ecdysteroid-Containing Squalenoylated Self-Assembling Nanoparticles Exert Tumor-Selective Sensitization to Reactive Oxygen Species (ROS)-Induced Oxidative Damage While Protecting Normal Cells: Implications for Selective Radiotherapy

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-28 DOI: 10.1021/acs.jmedchem.4c02758

Máté Vágvölgyi, Endre Kocsis, Bizhar A. Tayeb, István Zupkó, Renáta Minorics, Ana Martins, Zsófia Hoyk, Gergő Ballai, Imre Szenti, Zoltán Kónya, Tamás Gáti, Dóra Bogdán, Gábor Tóth, Attila Hunyadi

{"title":"Ecdysteroid-Containing Squalenoylated Self-Assembling Nanoparticles Exert Tumor-Selective Sensitization to Reactive Oxygen Species (ROS)-Induced Oxidative Damage While Protecting Normal Cells: Implications for Selective Radiotherapy","authors":"Máté Vágvölgyi, Endre Kocsis, Bizhar A. Tayeb, István Zupkó, Renáta Minorics, Ana Martins, Zsófia Hoyk, Gergő Ballai, Imre Szenti, Zoltán Kónya, Tamás Gáti, Dóra Bogdán, Gábor Tóth, Attila Hunyadi","doi":"10.1021/acs.jmedchem.4c02758","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02758","url":null,"abstract":"Central nervous system (CNS) tumors are exceptionally difficult to treat, and oxidative stress-inducing radiotherapy is an important treatment modality. In this study, we examined self-assembling pro-drug nanoconjugates of naturally derived antitumor ecdysteroids, which were designed to interfere with oxidative stress in brain tumor cells. Eight ecdysteroid-squalene conjugates were semi-synthesized and formulated into self-assembled aqueous nanosuspensions, which showed excellent stability for up to 16 weeks. The nanoassemblies demonstrated a strong dose-dependent sensitizing effect to tert-butyl hydroperoxide (tBHP)-induced oxidative damage in SH-SY5Y cells, while exerting a strong protective effect in MRC-5 fibroblast cells. In contrast, free ecdysteroids protected both cell lines from tBHP-induced damage. This suggests an important role for squalenoylation in the antitumor effect and indicates that our conjugates have potential as highly selective adjuvants in radiotherapy by sensitizing cancer cells and protecting surrounding tissues. Furthermore, our findings suggest a potential neuroprotective effect of nonconjugated ecdysteroids.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"125 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723629","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

Application of Machine Learning and Mechanistic Modeling to Predict Intravenous Pharmacokinetic Profiles in Humans

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-27 DOI: 10.1021/acs.jmedchem.5c00340

Xuelian Jia, Donato Teutonico, Saroj Dhakal, Yorgos M. Psarellis, Alexandra Abos, Hao Zhu, Panteleimon D. Mavroudis, Nikhil Pillai

{"title":"Application of Machine Learning and Mechanistic Modeling to Predict Intravenous Pharmacokinetic Profiles in Humans","authors":"Xuelian Jia, Donato Teutonico, Saroj Dhakal, Yorgos M. Psarellis, Alexandra Abos, Hao Zhu, Panteleimon D. Mavroudis, Nikhil Pillai","doi":"10.1021/acs.jmedchem.5c00340","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00340","url":null,"abstract":"Accurate prediction of new compounds’ pharmacokinetic (PK) profile in humans is crucial for drug discovery. Traditional methods, including allometric scaling and mechanistic modeling, rely on parameters from in vitro or in vivo testing, which are labor-intensive and involve ethical concerns. This study leverages machine learning (ML) to overcome these limitations by developing data-driven models. We compiled a large data set of small molecules’ physicochemical and PK properties from public sources and digitized human plasma concentration–time profiles for approximately 800 compounds from the literature. We introduced a hybrid modeling framework that combines ML with physiologically based pharmacokinetic modeling and a hierarchical ML framework that employs two steps of learning to directly estimate PK profiles. Tested on 106 drugs, these frameworks demonstrated prediction accuracies within a 2-fold and 5-fold error for 40–60% and 80%–90% of compounds, respectively, in both AUC and Cmax. Proposed approaches could enhance early molecular screening and design, advancing drug discovery capabilities.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713632","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

Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-27 DOI: 10.1021/acs.jmedchem.4c02064

Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue

{"title":"Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies","authors":"Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue","doi":"10.1021/acs.jmedchem.4c02064","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02064","url":null,"abstract":"Enhancement of the metabolic conversion of cyclophosphamide (CPA) increases its therapeutic effects. Activation of the human constitutive androstane receptor (hCAR) induces CYP2B6, a key enzyme responsible for CPA bioactivation. Based on our previous hCAR activator DL5016, we designed and synthesized a series of new hCAR activators. Compared to DL5016, three new compounds 6i, 6k (DL5055), and 7e, showed significantly improved activating potency for hCAR. Particularly, DL5055 activates hCAR with an EC50 of 0.35 μM and EMAX of 4.3, and does not activate hPXR and other related nuclear receptors. It induced the expression of CYP2B6 and caused the translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. DL5055 also induces the expression of Cyp2b10 (the mouse analog of human CYP2B6) in hCAR-transgenic mice. In addition, it significantly enhances the efficacy of CPA-based chemotherapy regimen, CHOP, in a coculture system and a mouse xenograft model in vivo.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"72 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713629","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 Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-27 DOI: 10.1021/acs.jmedchem.4c03035

Shuaishuai Xing, Jiheng Jiang, Xianglin Chu, Xiaolong Wang, Zhiqiang Wang, Xinyu Li, Bingbing Lv, Can Guo, Siyu He, Leyan Wang, Chenyu Zhang, Qinglong Guo, Li Zhao, Pengfei Fang, Feng Feng, Haopeng Sun

{"title":"Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma","authors":"Shuaishuai Xing, Jiheng Jiang, Xianglin Chu, Xiaolong Wang, Zhiqiang Wang, Xinyu Li, Bingbing Lv, Can Guo, Siyu He, Leyan Wang, Chenyu Zhang, Qinglong Guo, Li Zhao, Pengfei Fang, Feng Feng, Haopeng Sun","doi":"10.1021/acs.jmedchem.4c03035","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03035","url":null,"abstract":"Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound S07–2005 through a cascade virtual screening approach (AKR1C3 IC50 = 130 ± 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, 30 was optimized to adopt an “L”-shaped conformation targeting AKR1C3′s subpocket 1 (SP1) and oxyanion site (OS), enhancing inhibitory potency and selectivity (AKR1C3 IC50 = 5 ± 1 nM, SI > 2000). It enhanced sorafenib-induced ROS generation, promoted apoptosis, and restored sorafenib sensitivity in HCC models. In combination with sorafenib, compound 30 restored sorafenib sensitivity in HCC both in vitro and in vivo. Additionally, compound 30 demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713630","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

Advances in Sonodynamic Therapy: Focus on Ferroptosis.

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-03-27 Epub Date: 2025-03-10 DOI: 10.1021/acs.jmedchem.4c02603

Wendi Su, Hao Wang, Juhong Pan, Qing Zhou

引用次数: 0