Pub Date : 2025-11-25DOI: 10.1016/j.ejmech.2025.118400
Peiwen Han , Yuhao Jiang , Qing Ruan , Guangxing Yin , Qianna Wang , Junhong Feng , Dajie Ding , Qingna Xiao , Zuojie Li , Junbo Zhang
Dysregulated cyclin D-CDK4/6-Rb signalling drives uncontrolled proliferation in patients with breast cancer and other malignancies. Although CDK4/6 inhibitors improve patient outcomes, their efficacy is limited by resistance and toxicity, necessitating noninvasive monitoring tools. This review comprehensively analyses the development of radiolabelled CDK4/6 inhibitors for in vivo PET/SPECT imaging. Capitalizing on the solvent-exposed piperazine moiety, 18F-, 68Ga-, and 99mTc-labelled radiotracers achieve targeted visualization of CDK4/6 activity. However, more than 80% of radiotracers suffer from excessive hepatobiliary excretion and persistent blood retention. Strategic linker engineering, such as short alkyl chains and PEG spacers, mitigates steric hindrance from bulky chelators. Advances in one-step radiosynthesis and computational design address synthetic and pharmacokinetic challenges. Future efforts should focus on simplifying radiosynthesis protocols, optimizing pharmacokinetics to reduce nontargeted uptake, and integrating computational modelling (docking/dynamics) with experimental validation to refine linker design while advancing towards clinical trials. These innovations promise to transform precision oncology by enabling real-time therapy response assessment and early resistance detection.
{"title":"Advances in radiolabelled CDK4/6 inhibitors for in vivo imaging of CDK4/6 activity in tumours","authors":"Peiwen Han , Yuhao Jiang , Qing Ruan , Guangxing Yin , Qianna Wang , Junhong Feng , Dajie Ding , Qingna Xiao , Zuojie Li , Junbo Zhang","doi":"10.1016/j.ejmech.2025.118400","DOIUrl":"10.1016/j.ejmech.2025.118400","url":null,"abstract":"<div><div>Dysregulated cyclin D-CDK4/6-Rb signalling drives uncontrolled proliferation in patients with breast cancer and other malignancies. Although CDK4/6 inhibitors improve patient outcomes, their efficacy is limited by resistance and toxicity, necessitating noninvasive monitoring tools. This review comprehensively analyses the development of radiolabelled CDK4/6 inhibitors for <em>in vivo</em> PET/SPECT imaging. Capitalizing on the solvent-exposed piperazine moiety, <sup>18</sup>F-, <sup>68</sup>Ga-, and <sup>99m</sup>Tc-labelled radiotracers achieve targeted visualization of CDK4/6 activity. However, more than 80% of radiotracers suffer from excessive hepatobiliary excretion and persistent blood retention. Strategic linker engineering, such as short alkyl chains and PEG spacers, mitigates steric hindrance from bulky chelators. Advances in one-step radiosynthesis and computational design address synthetic and pharmacokinetic challenges. Future efforts should focus on simplifying radiosynthesis protocols, optimizing pharmacokinetics to reduce nontargeted uptake, and integrating computational modelling (docking/dynamics) with experimental validation to refine linker design while advancing towards clinical trials. These innovations promise to transform precision oncology by enabling real-time therapy response assessment and early resistance detection.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118400"},"PeriodicalIF":5.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.ejmech.2025.118384
Carlos D. García-Mejía , Julio César Almanza-Pérez , Luis Fernando Cofas-Vargas , Abigail Aragón-Morales , Antonio Nieto-Camacho , Enrique García-Hernández , Eduardo Hernández-Vázquez
A collection of xanthone-carbohydrate hybrids is reported as potential α-glucosidase inhibitors. The inhibitory activity of the xanthone core and the poly-hydroxylated commercially available drugs inspired the design of the compounds. Accordingly, both moieties were linked through a triazole core prepared by a copper-catalyzed alkyne-azide cycloaddition. After in vitro testing, compound 17f was identified as the most remarkable compound, with an IC50 of 14.9 ± 1.7 μM (acarbose had an IC50 of 7.3 ± 0.3 mM). Additionally, molecular docking studies suggested that the hybrids bind to the allosteric site, which explains the non-competitive or mixed inhibition found in enzymatic kinetics; the stability of the complex was confirmed through molecular dynamics simulation. Furthermore, an oral sucrose tolerance test (OSTT) in both healthy and diabetic mice demonstrated that benzoxanthone derivatives 17f and 18f prevent the hyperglycemic peak that occurs after sucrose administration. Although α-glucosidase inhibition is a key mechanism of action for xanthone 17f, it also improved plasma glucose levels after 60 min of sucrose administration in diabetic mice, resulting in a decrease of 42 % compared to initial glucose levels and showing better reduction than acarbose (reduction of 22 %), suggesting a complementary antidiabetic effect.
{"title":"Triazole-containing xanthone-furanose/pyranose hybrids: synthesis of potential α-glucosidase inhibitors","authors":"Carlos D. García-Mejía , Julio César Almanza-Pérez , Luis Fernando Cofas-Vargas , Abigail Aragón-Morales , Antonio Nieto-Camacho , Enrique García-Hernández , Eduardo Hernández-Vázquez","doi":"10.1016/j.ejmech.2025.118384","DOIUrl":"10.1016/j.ejmech.2025.118384","url":null,"abstract":"<div><div>A collection of xanthone-carbohydrate hybrids is reported as potential α-glucosidase inhibitors. The inhibitory activity of the xanthone core and the poly-hydroxylated commercially available drugs inspired the design of the compounds. Accordingly, both moieties were linked through a triazole core prepared by a copper-catalyzed alkyne-azide cycloaddition. After <em>in vitro</em> testing, compound <strong>17f</strong> was identified as the most remarkable compound, with an IC<sub>50</sub> of 14.9 ± 1.7 μM (acarbose had an IC<sub>50</sub> of 7.3 ± 0.3 mM). Additionally, molecular docking studies suggested that the hybrids bind to the allosteric site, which explains the non-competitive or mixed inhibition found in enzymatic kinetics; the stability of the complex was confirmed through molecular dynamics simulation. Furthermore, an oral sucrose tolerance test (OSTT) in both healthy and diabetic mice demonstrated that benzoxanthone derivatives <strong>17f</strong> and <strong>18f</strong> prevent the hyperglycemic peak that occurs after sucrose administration. Although α-glucosidase inhibition is a key mechanism of action for xanthone <strong>17f</strong>, it also improved plasma glucose levels after 60 min of sucrose administration in diabetic mice, resulting in a decrease of 42 % compared to initial glucose levels and showing better reduction than acarbose (reduction of 22 %), suggesting a complementary antidiabetic effect.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118384"},"PeriodicalIF":5.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.ejmech.2025.118388
Tomáš Otava , Matúš Drexler , Petra Krafčíková , Dominika Chalupská , Karel Chalupský , Václav Veverka , Evzen Boura , Radim Nencka
Emerging viral pathogens highlight the need for targeted antiviral strategies, particularly against mechanistically validated enzymes like the Dengue virus NS5 methyltransferase - an essential component of viral RNA capping and immune evasion. Despite its therapeutic relevance, the discovery of potent small-molecule inhibitors has been constrained by the absence of robust complementary assays. In this study, we address this gap through a comparative evaluation of three orthogonal methodologies that enable comprehensive identification and characterization of inhibitors targeting this enzyme. We synthesized a focused library of thirty S-adenosylhomocysteine analogs via copper-catalyzed azide–alkyne cycloaddition and screened them using three orthogonal methods: (i) fluorescence polarization to monitor ligand displacement from the methyl donor site; (ii) NMR titration to resolve residue-specific interactions; and (iii) a label-free enzymatic assay employing acoustic mass spectrometry to quantify the inhibition of methyl group transfer. Consistent potency rankings across all platforms validated this approach. The fluorescence assay enabled high-throughput triaging, NMR provided structural insight into ligand binding, and enzymatic profiling confirmed functional inhibition. This integrated, modular screening strategy enables the rational development of NS5 methyltransferase inhibitors and is adaptable to related RNA-capping enzymes of viral or other origin.
{"title":"Exploring advanced methodologies for NS5 methyltransferase targeted drug discovery","authors":"Tomáš Otava , Matúš Drexler , Petra Krafčíková , Dominika Chalupská , Karel Chalupský , Václav Veverka , Evzen Boura , Radim Nencka","doi":"10.1016/j.ejmech.2025.118388","DOIUrl":"10.1016/j.ejmech.2025.118388","url":null,"abstract":"<div><div>Emerging viral pathogens highlight the need for targeted antiviral strategies, particularly against mechanistically validated enzymes like the Dengue virus NS5 methyltransferase - an essential component of viral RNA capping and immune evasion. Despite its therapeutic relevance, the discovery of potent small-molecule inhibitors has been constrained by the absence of robust complementary assays. In this study, we address this gap through a comparative evaluation of three orthogonal methodologies that enable comprehensive identification and characterization of inhibitors targeting this enzyme. We synthesized a focused library of thirty <em>S</em>-adenosylhomocysteine analogs via copper-catalyzed azide–alkyne cycloaddition and screened them using three orthogonal methods: (i) fluorescence polarization to monitor ligand displacement from the methyl donor site; (ii) NMR titration to resolve residue-specific interactions; and (iii) a label-free enzymatic assay employing acoustic mass spectrometry to quantify the inhibition of methyl group transfer. Consistent potency rankings across all platforms validated this approach. The fluorescence assay enabled high-throughput triaging, NMR provided structural insight into ligand binding, and enzymatic profiling confirmed functional inhibition. This integrated, modular screening strategy enables the rational development of NS5 methyltransferase inhibitors and is adaptable to related RNA-capping enzymes of viral or other origin.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118388"},"PeriodicalIF":5.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-22DOI: 10.1016/j.ejmech.2025.118389
Wenjie Liu , Limeng Wu , Xi Zeng , Huanhua Chen , Xinyue Ning , Xiaoyu Sun , Wenqiang Xuan , Ying Hao , Hongli Jia , Zhenshu Li , Zonghe Xu , Xinyu Li , Zihua Xu , Wenwu Liu , Qingchun Zhao , Shuang Hao
Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Glycogen synthase kinase 3β (GSK3β), a key enzyme in tau phosphorylation, is a promising therapeutic target for AD. Herein, we employed a structure-based drug design strategy to develop a novel series of harmine derivatives as potent GSK3β inhibitors. Among them, compound 39a bearing an intramolecular hydrogen bond scaffold, showed potent GSK3β inhibition (IC50 = 0.37 nM), meanwhile maintaining remarkable kinase selectivity, including >25000-fold selectivity over dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a well-known target of β-carboline derivative harmine. It suppressed tau phosphorylation in Tau (P301L) 293T cells (EC50 = 0.06 ± 0.01 μM) and exhibited favorable blood-brain barrier permeability. Notably, 39a significantly attenuated cognitive deficits and tau hyperphosphorylation pathology in OA-induced C57BL/6J mice and 3 × Tg-AD mouse models, without causing spontaneous locomotor defects at therapeutic doses. Collectively, 39a emerges as a promising GSK3β inhibitor for probing GSK3β′s role in AD pathogenesis and guiding anti-AD drug discovery.
{"title":"Discovery of novel harmine derivatives as potent, selective, and brain permeable GSK3β inhibitors with effective In vivo anti-AD activity","authors":"Wenjie Liu , Limeng Wu , Xi Zeng , Huanhua Chen , Xinyue Ning , Xiaoyu Sun , Wenqiang Xuan , Ying Hao , Hongli Jia , Zhenshu Li , Zonghe Xu , Xinyu Li , Zihua Xu , Wenwu Liu , Qingchun Zhao , Shuang Hao","doi":"10.1016/j.ejmech.2025.118389","DOIUrl":"10.1016/j.ejmech.2025.118389","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Glycogen synthase kinase 3β (GSK3β), a key enzyme in tau phosphorylation, is a promising therapeutic target for AD. Herein, we employed a structure-based drug design strategy to develop a novel series of harmine derivatives as potent GSK3β inhibitors. Among them, compound <strong>39a</strong> bearing an intramolecular hydrogen bond scaffold, showed potent GSK3β inhibition (IC<sub>50</sub> = 0.37 nM), meanwhile maintaining remarkable kinase selectivity, including >25000-fold selectivity over dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a well-known target of <em>β</em>-carboline derivative harmine. It suppressed tau phosphorylation in Tau (P301L) 293T cells (EC<sub>50</sub> = 0.06 ± 0.01 μM) and exhibited favorable blood-brain barrier permeability. Notably, <strong>39a</strong> significantly attenuated cognitive deficits and tau hyperphosphorylation pathology in OA-induced C57BL/6J mice and 3 × Tg-AD mouse models, without causing spontaneous locomotor defects at therapeutic doses. Collectively, <strong>39a</strong> emerges as a promising GSK3β inhibitor for probing GSK3β′s role in AD pathogenesis and guiding anti-AD drug discovery.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118389"},"PeriodicalIF":5.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π–π and alkyl–π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood–brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.
{"title":"Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study","authors":"Antonija Jelčić , Stanislava Talić , Ilijana Odak , Milena Mlakić , Zlata Lasić , Sunčica Roca , Ivana Šagud , Tea Bruketa , Martina Bosnar , Danijela Barić , Irena Škorić","doi":"10.1016/j.ejmech.2025.118375","DOIUrl":"10.1016/j.ejmech.2025.118375","url":null,"abstract":"<div><div>A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs <em>via</em> a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC<sub>50</sub> values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound <strong>13</strong>, bearing a pyrrolidine moiety, exhibited an IC<sub>50</sub> value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π–π and alkyl–π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. <em>In silico</em> ADME(T) analysis predicted excellent intestinal absorption, blood–brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. <em>In vitro</em> cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound <strong>13</strong>, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118375"},"PeriodicalIF":5.9,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ejmech.2025.118373
Soumitra Guin , Kathryn M. Alden , Emily Harshbarger , Laurie C. Ristow , Andrew J. Jezewski , Damian J. Krysan , Marvin J. Meyers
With millions of cases reported annually, fungal infections represent a growing public health concern. The effectiveness of current treatment options is hindered by the availability of only three antifungal drug classes, rising resistance, and suboptimal efficacy against certain pathogens. One promising strategy to overcome these challenges is to enhance the antifungal activity of existing drugs while maintaining favorable pharmacokinetic profiles. Herein, we describe the repurposing and optimization of a series of phenoxazine analogs of the antipsychotic drugs fluphenazine and trifluoperazine as antifungals. Optimization and the structure activity relationship studies identified novel phenoxazine derivatives as potent antifungal agents against Cryptococcus neoformans and Candida albicans (MIC 1–4 μg/mL and 2–8 μg/mL, respectively, 4–16 fold more potent than fluphenazine and trifluoperazine). In addition, the POZ analogs displayed reduced affinities towards serotonin and dopamine receptors compared to trifluoperazine. However, potent and moderately selective POZ analog 61 failed to demonstrate efficacy in a mouse model of cryptococcosis, demonstrating the need for further optimization.
{"title":"Second generation repurposing of phenothiazine antipsychotic drugs as antifungal lead molecules via optimization of phenoxazine derivatives","authors":"Soumitra Guin , Kathryn M. Alden , Emily Harshbarger , Laurie C. Ristow , Andrew J. Jezewski , Damian J. Krysan , Marvin J. Meyers","doi":"10.1016/j.ejmech.2025.118373","DOIUrl":"10.1016/j.ejmech.2025.118373","url":null,"abstract":"<div><div>With millions of cases reported annually, fungal infections represent a growing public health concern. The effectiveness of current treatment options is hindered by the availability of only three antifungal drug classes, rising resistance, and suboptimal efficacy against certain pathogens. One promising strategy to overcome these challenges is to enhance the antifungal activity of existing drugs while maintaining favorable pharmacokinetic profiles. Herein, we describe the repurposing and optimization of a series of phenoxazine analogs of the antipsychotic drugs fluphenazine and trifluoperazine as antifungals. Optimization and the structure activity relationship studies identified novel phenoxazine derivatives as potent antifungal agents against <em>Cryptococcus neoformans</em> and <em>Candida albicans</em> (MIC 1–4 μg/mL and 2–8 μg/mL, respectively, 4–16 fold more potent than fluphenazine and trifluoperazine). In addition, the POZ analogs displayed reduced affinities towards serotonin and dopamine receptors compared to trifluoperazine. However, potent and moderately selective POZ analog <strong>61</strong> failed to demonstrate efficacy in a mouse model of cryptococcosis, demonstrating the need for further optimization.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118373"},"PeriodicalIF":5.9,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.ejmech.2025.118369
Vittorio Canale , Klaudia Blicharz-Futera , Monika Bijata , Natalie G. Cavalco , Anna Partyka , Matylda Stefaniak , Michał Kamiński , Grzegorz Satała , Dawid Warszycki , Janelle K. Lanham , Joanna Gołębiowska , Maciej Gawlik , Magdalena Smolik , Krystian Bijata , Magdalena Jastrzębska-Więsek , Rafał Kurczab , Andrzej J. Bojarski , Maria Walczak , John D. McCorvy , Jakub Włodarczyk , Paweł Zajdel
Affective disorders, the leading causes of disability and premature death worldwide, require new and effective treatment strategies. Clinically used antidepressants and second-generation antipsychotic drugs, including vortioxetine and lurasidone, act as potent 5-HT7 receptor antagonists and improve cognitive functions in the patients with mood disorders. Additionally, 5-HT7 receptor-mediated activation of matrix metalloproteinase 9 (MMP-9) induces depressive-like behavior in mice. We designed and synthesized a series of 27 arylsulfonamide derivatives of 2-[(2-aryl/2-heteroaryl)phenoxy]ethyl-piperidines and examined their in vitro and in vivo effects. These compounds are closely related to the previously reported 5-HT7 receptor ligand (PZ-1129), developed in our laboratories. Our goal was to investigate the impact of heterocyclic ring replacement on receptor selectivity and metabolic stability, because the aryloxyl moiety was postulated to determine affinity for serotonin and dopamine receptors, and interactions with metabolizing enzymes. The study identified compound 57 as a potent, selective and metabolically stable 5-HT7 receptor inverse agonist of Gs signaling pathway. Bioavailable compound 57 shortened immobility in the forced swim test in mice and reversed PCP-induced cognitive deficits in the novel object recognition test in rats suggesting antidepressant-like and pro-cognitive effects. In addition, compound 57 reduced 5-HT7 receptor-mediated MMP-9 activity in the mouse hippocampus with efficacy comparable to the reference 5-HT7 receptor antagonist, SB-269970, further suggesting its purported antidepressant-like actions. These findings support the potential therapeutic application of targeting 5-HT7 receptor/MMP-9 signaling pathway for the treatment of affective disorders.
{"title":"Fine-tuning 5-HT7 receptor selectivity, inverse agonism, and metabolic stability of new (aryloxy)ethyl-piperidines toward antidepressant and pro-cognitive properties","authors":"Vittorio Canale , Klaudia Blicharz-Futera , Monika Bijata , Natalie G. Cavalco , Anna Partyka , Matylda Stefaniak , Michał Kamiński , Grzegorz Satała , Dawid Warszycki , Janelle K. Lanham , Joanna Gołębiowska , Maciej Gawlik , Magdalena Smolik , Krystian Bijata , Magdalena Jastrzębska-Więsek , Rafał Kurczab , Andrzej J. Bojarski , Maria Walczak , John D. McCorvy , Jakub Włodarczyk , Paweł Zajdel","doi":"10.1016/j.ejmech.2025.118369","DOIUrl":"10.1016/j.ejmech.2025.118369","url":null,"abstract":"<div><div>Affective disorders, the leading causes of disability and premature death worldwide, require new and effective treatment strategies. Clinically used antidepressants and second-generation antipsychotic drugs, including vortioxetine and lurasidone, act as potent 5-HT<sub>7</sub> receptor antagonists and improve cognitive functions in the patients with mood disorders. Additionally, 5-HT<sub>7</sub> receptor-mediated activation of matrix metalloproteinase 9 (MMP-9) induces depressive-like behavior in mice. We designed and synthesized a series of 27 arylsulfonamide derivatives of 2-[(2-aryl/2-heteroaryl)phenoxy]ethyl-piperidines and examined their <em>in vitro</em> and <em>in vivo</em> effects. These compounds are closely related to the previously reported 5-HT<sub>7</sub> receptor ligand (PZ-1129), developed in our laboratories. Our goal was to investigate the impact of heterocyclic ring replacement on receptor selectivity and metabolic stability, because the aryloxyl moiety was postulated to determine affinity for serotonin and dopamine receptors, and interactions with metabolizing enzymes. The study identified compound <strong>57</strong> as a potent, selective and metabolically stable 5-HT<sub>7</sub> receptor inverse agonist of Gs signaling pathway. Bioavailable compound <strong>57</strong> shortened immobility in the forced swim test in mice and reversed PCP-induced cognitive deficits in the novel object recognition test in rats suggesting antidepressant-like and pro-cognitive effects. In addition, compound <strong>57</strong> reduced 5-HT<sub>7</sub> receptor-mediated MMP-9 activity in the mouse hippocampus with efficacy comparable to the reference 5-HT<sub>7</sub> receptor antagonist, SB-269970, further suggesting its purported antidepressant-like actions. These findings support the potential therapeutic application of targeting 5-HT<sub>7</sub> receptor/MMP-9 signaling pathway for the treatment of affective disorders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118369"},"PeriodicalIF":5.9,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.ejmech.2025.118385
Victoria Banas , Kuljeet Seehra , Matthew Mahoney , Carolina Alisio , Yevhenii Kyriukha , Elizabeth Weiland , Michelle Fath , Zhenfu Han , Traci Bricker , Michael Tartell , Sean Whelan , Adrianus C.M. Boon , James W. Janetka
TMPRSS2 is a membrane associated serine protease which is important in the viral pathogenesis of coronaviruses and influenza viruses. We developed mechanism-based covalent α-ketobenzothiazole (kbt) inhibitors using substrate specificity PS-SCL screening of TMPRSS2 as a rational guide for inhibitor design. Three distinct focused libraries of tetrapeptide kbts were synthesized and evaluated for their inhibition of TMPRSS2, matriptase and other serine proteases. We also investigated different capping groups for the previously reported tripeptide inhibitor Ac-QFR-kbt (18) to increase its selectivity over the blood coagulation protease factor Xa. The most potent compounds were tested for their ability to inhibit viral replication of SARS-CoV-2 coronavirus and the H1N1 influenza A virus. The most active compounds were profiled for their pharmacokinetics (PK) in mice. Several promising new compounds were identified with improved potency, selectivity, and drug-like properties including Bz-QFR-kbt (23) and Cbz-QFR-kbt (25) with an IC50 of 150 nM and 60 nM for H1N1, respectively.
{"title":"Inhibitors of membrane associated serine proteases block replication of coronavirus SARS-CoV-2 and influenza virus H1N1","authors":"Victoria Banas , Kuljeet Seehra , Matthew Mahoney , Carolina Alisio , Yevhenii Kyriukha , Elizabeth Weiland , Michelle Fath , Zhenfu Han , Traci Bricker , Michael Tartell , Sean Whelan , Adrianus C.M. Boon , James W. Janetka","doi":"10.1016/j.ejmech.2025.118385","DOIUrl":"10.1016/j.ejmech.2025.118385","url":null,"abstract":"<div><div>TMPRSS2 is a membrane associated serine protease which is important in the viral pathogenesis of coronaviruses and influenza viruses. We developed mechanism-based covalent α-ketobenzothiazole (kbt) inhibitors using substrate specificity PS-SCL screening of TMPRSS2 as a rational guide for inhibitor design. Three distinct focused libraries of tetrapeptide kbts were synthesized and evaluated for their inhibition of TMPRSS2, matriptase and other serine proteases. We also investigated different capping groups for the previously reported tripeptide inhibitor Ac-QFR-kbt (<strong>18</strong>) to increase its selectivity over the blood coagulation protease factor Xa. The most potent compounds were tested for their ability to inhibit viral replication of SARS-CoV-2 coronavirus and the H1N1 influenza A virus. The most active compounds were profiled for their pharmacokinetics (PK) in mice. Several promising new compounds were identified with improved potency, selectivity, and drug-like properties including Bz-QFR-kbt (<strong>23</strong>) and Cbz-QFR-kbt (<strong>25</strong>) with an IC<sub>50</sub> of 150 nM and 60 nM for H1N1, respectively.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118385"},"PeriodicalIF":5.9,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.ejmech.2025.118387
Kun Huang , Peng Luo , Cai-Hua Li , Nan Huang , Kun Yao , Xiong-Xiong Lan , Ling-Feng Du , Yan Miao , Qing Tang , Ying Xu , Yong-Xia Zhu , Ning-Yu Wang
Cereblon (CRBN), the target of immunomodulatory drugs (IMiDs) such as thalidomide and lenalidomide, serves as the substrate recognition subunit of the CRL4CRBN E3 ubiquitin ligase complex. This E3 ligase is widely expressed across multiple human tissues and organs, and is commonly utilized in PROTAC design. However, PROTACs derived from classical IMiD-based CRBN ligands face several limitations, including the risk of teratogenicity due to the degradation of CRBN neosubstrates, such as SALL4, and suboptimal drug metabolism and pharmacokinetic (DMPK) properties resulting from the hydrolytic susceptibility of the IMiD scaffold. Therefore, the development of novel chemotypes of CRBN ligands is important for advancing PROTAC development. In this study, we developed novel unnatural dipeptide CRBN ligands for designing PROTAC targeting BRD4 and ALK, the resulting PROTACs demonstrated potent protein degradation and antiproliferative activities, exhibiting comparable or superior efficacy to IMiD-based PROTACs. Our study demonstrated that: (i) dipeptide CRBN ligands-based PROTACs were well tolerated to unnatural hydrophobic amino acids at the N-1 position; (ii) unnatural cyclic imide dipeptides could serve as versatile CRBN ligands for PROTACs design cross distinct targets; and (iii) unnatural dipeptide PROTACs attenuated degradation of IMiD-associated neosubstrates but induced degradation of novel CRBN neosubstrates. Collectively, these unnatural dipeptide CRBN ligands would expand the chemical space and target scope of CRBN-recruiting PROTACs, and they also showed potential for developing molecular glues targeting more proteins.
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