ACS Pharmacology and Translational Science最新文献

{"title":"The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents","authors":"Anders A. Jensen,&nbsp;Claudia R. Cecchi,&nbsp;Meghan Hibicke,&nbsp;Astrid H. Bach,&nbsp;Erik Kaadt,&nbsp;Emil Märcher-Rørsted,&nbsp;Charles D. Nichols,&nbsp;Betina Elfving and Jesper L. Kristensen*,&nbsp;","doi":"10.1021/acsptsci.5c0020810.1021/acsptsci.5c00208","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00208https://doi.org/10.1021/acsptsci.5c00208","url":null,"abstract":"<p >Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed pharmacological characterization of one such compound, LPH-5 [(<i>S</i>)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT_2A receptor (5-HT_2AR) with pronounced selectivity for 5-HT_2AR over the related 5-HT_2BR and 5-HT_2CR in a range of functional assays. LPH-5 dose-dependently induced head-twitch responses (HTR) as well as robust acute and persistent antidepressant-like effects in rats. These results suggest that selective 5-HT_2AR activation holds antidepressant potential and indicate that this activity component is key for the therapeutics effects of classical psychedelics.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1791–1803 1791–1803"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis.","authors":"Qi-Xin Guan, Long-Bo Yu, Peng Wang, Qing-Yuan Hu, Cai-Ping Tan","doi":"10.1021/acsptsci.5c00219","DOIUrl":"10.1021/acsptsci.5c00219","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (<b>Ti-DFX-TPP</b>) to disrupt iron homeostasis in TNBC cells through transmetalation. <b>Ti-DFX-TPP</b> depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by <b>Ti-DFX-TPP</b> increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that <b>Ti-DFX-TPP</b> inhibits tumor growth without significant toxicity to major organs. These findings suggest that <b>Ti-DFX-TPP</b> is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1804-1813"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modernizing Preclinical Drug Development: The Role of New Approach Methodologies","authors":"Krina Mehta*,&nbsp;Christian Maass,&nbsp;Lourdes Cucurull-Sanchez,&nbsp;Cesar Pichardo-Almarza,&nbsp;Kalyanasundaram Subramanian,&nbsp;Ioannis P. Androulakis,&nbsp;Jogarao Gobburu,&nbsp;Stephan Schaller and Catherine M Sherwin,&nbsp;","doi":"10.1021/acsptsci.5c0016210.1021/acsptsci.5c00162","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00162https://doi.org/10.1021/acsptsci.5c00162","url":null,"abstract":"<p >Over 90% of investigational drugs fail during clinical development, largely due to poor translation of pharmacokinetic, efficacy, and toxicity data from preclinical to clinical settings. The high costs and ethical concerns associated with translational failures highlight the need for more efficient and reliable preclinical tools. Human-relevant new approach methodologies (NAMs), including advanced in vitro systems, in silico mechanistic models, and computational techniques like artificial intelligence and machine learning, can improve translational success, as evident by several literature examples. Case studies on physiologically based pharmacokinetic modeling and quantitative systems pharmacology applications demonstrate the potential of NAMs in improving translational accuracy, reducing reliance on animal studies. Additionally, mechanistic modeling approaches for drug-induced liver injury and tumor microenvironment models have provided critical insights into drug safety and efficacy. We propose a structured and iterative “a priori in silico” workflow that integrates NAM components to actively guide preclinical study design─a step toward more predictive and resource-efficient drug development. The proposed workflow can enable in vivo predictions to guide the design of reduced and optimal preclinical studies. The findings from these preclinical studies can then be used to refine computational models to enhance the accuracy of human predictions or guide additional preclinical studies, as needed. To conclude, integrating computational and in vitro NAM approaches can optimize preclinical drug development, improving translational accuracy and reducing clinical trial failures. This paradigm shift is further supported by global regulations, such as the FDA Modernization Act 2.0 and EMA directive 2010/63/EU, underscoring the regulatory momentum toward adopting human-relevant NAMs as the new standard in preclinical drug development.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1513–1525 1513–1525"},"PeriodicalIF":4.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Tuning of Cyanine 5 Dyes to Improve the Pharmacokinetic Profile of Nanobody-Based Fluorescent Tracers","authors":"Łukasz Mateusiak*,&nbsp;Dora M. Chigoho,&nbsp;Sam Floru,&nbsp;Sofie Pollenus,&nbsp;Pieterjan Debie,&nbsp;Danny M. van Willigen,&nbsp;Fijs W. B. van Leeuwen and Sophie Hernot*,&nbsp;","doi":"10.1021/acsptsci.5c0002410.1021/acsptsci.5c00024","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00024https://doi.org/10.1021/acsptsci.5c00024","url":null,"abstract":"<p >Over the past two decades, it has become evident that fluorescence imaging holds substantial value in preclinical research and could also play a pivotal role in clinical applications such as intraoperative molecular imaging. The latter relies on applying targeted fluorescent agents designed to recognize specific biomarkers expressed in diseased tissues. Targeting moieties, such as camelid-derived nanobodies (Nbs), exhibit remarkable pharmacokinetics for molecular imaging owing to their robustness and compact size. However, the relatively small size of Nbs makes their pharmacokinetics sensitive to the chemical structure of attached fluorophores. In this study, we conducted a comparative analysis between Nbs labeled with three different sulfoCy5 derivatives (Cy5^2– (charge −2), Cy5^– (charge −1), and Cy5° (charge 0)). Nb-Cy5^2– and Nb-Cy5° allowed specific <i>in vivo</i> visualization of subcutaneous tumors in mice within 1 h with minimal background. Conversely, Nb-Cy5^– required at least 3 h to achieve sufficient contrast and exhibited nonspecific liver accumulation. Remarkably, Nb-Cy5^2– was able to overcome the renal retention typically observed for Nbs. Microscopy analyses of kidney sections revealed differential accumulation for Nb-Cy5^2– and Nb-Cy5° at the level of the proximal tubule cells, with only Nb-Cy5^2– showing internalization in lysosomes and endosomes and subsequent metabolization. In conclusion, this study underscores the significant influence of dye charges on the biodistribution profile and tumor-targeting capabilities of Nb tracers. Among the tested variants, the fluorescent dye Cy5^2– emerged as a promising choice to use in combination with Nbs for molecular imaging applications, in particular due to its low renal retention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1659–1668 1659–1668"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Tuning of Cyanine 5 Dyes to Improve the Pharmacokinetic Profile of Nanobody-Based Fluorescent Tracers.","authors":"Łukasz Mateusiak, Dora M Chigoho, Sam Floru, Sofie Pollenus, Pieterjan Debie, Danny M van Willigen, Fijs W B van Leeuwen, Sophie Hernot","doi":"10.1021/acsptsci.5c00024","DOIUrl":"10.1021/acsptsci.5c00024","url":null,"abstract":"<p><p>Over the past two decades, it has become evident that fluorescence imaging holds substantial value in preclinical research and could also play a pivotal role in clinical applications such as intraoperative molecular imaging. The latter relies on applying targeted fluorescent agents designed to recognize specific biomarkers expressed in diseased tissues. Targeting moieties, such as camelid-derived nanobodies (Nbs), exhibit remarkable pharmacokinetics for molecular imaging owing to their robustness and compact size. However, the relatively small size of Nbs makes their pharmacokinetics sensitive to the chemical structure of attached fluorophores. In this study, we conducted a comparative analysis between Nbs labeled with three different sulfoCy5 derivatives (Cy5^2- (charge -2), Cy5^- (charge -1), and Cy5° (charge 0)). Nb-Cy5^2- and Nb-Cy5° allowed specific <i>in vivo</i> visualization of subcutaneous tumors in mice within 1 h with minimal background. Conversely, Nb-Cy5^- required at least 3 h to achieve sufficient contrast and exhibited nonspecific liver accumulation. Remarkably, Nb-Cy5^2- was able to overcome the renal retention typically observed for Nbs. Microscopy analyses of kidney sections revealed differential accumulation for Nb-Cy5^2- and Nb-Cy5° at the level of the proximal tubule cells, with only Nb-Cy5^2- showing internalization in lysosomes and endosomes and subsequent metabolization. In conclusion, this study underscores the significant influence of dye charges on the biodistribution profile and tumor-targeting capabilities of Nb tracers. Among the tested variants, the fluorescent dye Cy5^2- emerged as a promising choice to use in combination with Nbs for molecular imaging applications, in particular due to its low renal retention.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1659-1668"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-Targeted Titanium Complex Exerts Potent Anticancer Activity by Disturbing Iron Homeostasis","authors":"Qi-Xin Guan,&nbsp;Long-Bo Yu,&nbsp;Peng Wang,&nbsp;Qing-yuan Hu* and Cai-Ping Tan*,&nbsp;","doi":"10.1021/acsptsci.5c0021910.1021/acsptsci.5c00219","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00219https://doi.org/10.1021/acsptsci.5c00219","url":null,"abstract":"<p >Triple-negative breast cancer (TNBC) is an aggressive malignancy, with limited targeted treatment options. In this study, we developed a novel triphenylphosphine (TPP)-modified deferasirox (DFX) titanium complex (<b>Ti-DFX-TPP</b>) to disrupt iron homeostasis in TNBC cells through transmetalation. <b>Ti-DFX-TPP</b> depletes the labile iron pool, triggering a compensatory upregulation of transferrin receptor 1 (TfR1) in response to an intracellular iron deficiency. The disruption of iron metabolism by <b>Ti-DFX-TPP</b> increases reactive oxygen species (ROS) levels, which in turn lead to mitochondrial dysfunction and DNA damage, ultimately inhibiting cancer cell growth. In vivo studies further demonstrated that <b>Ti-DFX-TPP</b> inhibits tumor growth without significant toxicity to major organs. These findings suggest that <b>Ti-DFX-TPP</b> is a promising therapeutic candidate for TNBC, as it exploits the disruption of iron metabolism and ROS pathways to enhance its anticancer efficacy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1804–1813 1804–1813"},"PeriodicalIF":4.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteins from Stressed Mesenchymal Stem Cells Can Repair Hair Follicles and Promote Hair Regeneration","authors":"Minghao Xu,&nbsp;Lu Diao,&nbsp;Xiangxiang Xu,&nbsp;Ao Zhu,&nbsp;Yu Wang and Mi Liu*,&nbsp;","doi":"10.1021/acsptsci.5c0018410.1021/acsptsci.5c00184","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00184https://doi.org/10.1021/acsptsci.5c00184","url":null,"abstract":"<p >Androgenetic alopecia (AGA) is the most prevalent type of hair loss in the clinic. Corticosteroids are the most widely used agents for hair loss treatment. However, the long-term use of hormonal drugs is associated with various side effects. Therefore, new treatment methods are urgently needed. In this study, we found that proteins derived from stressed mesenchymal stem cells (PDSSCs) can be utilized to treat AGA in a mouse model. Secretion from chemically stimulated mesenchymal stem cells (MSCs) can reverse hair loss through immune regulation and anti-inflammatory functions. Herein, the root extract of Atalantia monophylla is utilized to stimulate MSCs to produce stress proteins with immunomodulatory function, and thus, proteins derived from stressed MSCs (PDSSCs) can be obtained from stimulated MSCs. We found that PDSSCs successfully boosted hair growth and activated hair follicle (HF) stem cells, thereby inducing hair regeneration in an AGA mouse model. PDSSCs achieved this effect through the Wnt pathway and the TGF-β pathway. Our research is the first to illustrate that stressed-MSC therapy can improve hair regeneration in AGA mice. Overall, this study demonstrated that utilizing PDSSCs from MSCs stimulated with the root extract of Atalantia monophylla to treat AGA is a promising strategy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1768–1777 1768–1777"},"PeriodicalIF":4.9,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteins from Stressed Mesenchymal Stem Cells Can Repair Hair Follicles and Promote Hair Regeneration.","authors":"Minghao Xu, Lu Diao, Xiangxiang Xu, Ao Zhu, Yu Wang, Mi Liu","doi":"10.1021/acsptsci.5c00184","DOIUrl":"10.1021/acsptsci.5c00184","url":null,"abstract":"<p><p>Androgenetic alopecia (AGA) is the most prevalent type of hair loss in the clinic. Corticosteroids are the most widely used agents for hair loss treatment. However, the long-term use of hormonal drugs is associated with various side effects. Therefore, new treatment methods are urgently needed. In this study, we found that proteins derived from stressed mesenchymal stem cells (PDSSCs) can be utilized to treat AGA in a mouse model. Secretion from chemically stimulated mesenchymal stem cells (MSCs) can reverse hair loss through immune regulation and anti-inflammatory functions. Herein, the root extract of Atalantia monophylla is utilized to stimulate MSCs to produce stress proteins with immunomodulatory function, and thus, proteins derived from stressed MSCs (PDSSCs) can be obtained from stimulated MSCs. We found that PDSSCs successfully boosted hair growth and activated hair follicle (HF) stem cells, thereby inducing hair regeneration in an AGA mouse model. PDSSCs achieved this effect through the Wnt pathway and the TGF-β pathway. Our research is the first to illustrate that stressed-MSC therapy can improve hair regeneration in AGA mice. Overall, this study demonstrated that utilizing PDSSCs from MSCs stimulated with the root extract of Atalantia monophylla to treat AGA is a promising strategy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1768-1777"},"PeriodicalIF":4.9,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction","authors":"Perihan A. Elzahhar,&nbsp;Hisham A. Nematalla,&nbsp;Malak A. Abouayana,&nbsp;El Sayed H. El Ashry,&nbsp;Mahmoud Balbaa,&nbsp;Andrea Petreni,&nbsp;Rasha Nassra,&nbsp;Hend A. Yassin,&nbsp;Yasmine N. Kamel,&nbsp;Mohamed A. Elrewiny,&nbsp;Mahmoud A. Agami,&nbsp;Monica Makkar,&nbsp;Minh Sai,&nbsp;Daniel Merk*,&nbsp;Hala F. Labib,&nbsp;Rosaria Spagnuolo,&nbsp;Marina Naldi,&nbsp;Manuela Bartolini,&nbsp;Soad A. El-Hawash*,&nbsp;Claudiu T. Supuran*,&nbsp;Ahmed S. F. Belal* and Ahmed F. El-Yazbi*,&nbsp;","doi":"10.1021/acsptsci.5c0001110.1021/acsptsci.5c00011","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00011https://doi.org/10.1021/acsptsci.5c00011","url":null,"abstract":"<p >In light of the significant correlation between inflammatory alterations and metabolic dysfunction throughout different stages of metabolic disease progression, we focused on utilizing our previously characterized glitazone-derived anti-inflammatory 1,2,3-triazoles as lead compounds to create new multitarget directed ligands that interact with COX-2, peroxisome proliferator-activated receptor γ (PPARγ), and CA within the framework of metabolic disorders. Notably, seven compounds exhibited equivalent or similar COX-2 inhibitory effects to celecoxib. Four compounds, namely, <b>3b</b>, <b>3e</b>, <b>5e</b>, and <b>5h</b>, exhibited substantial nanomolar inhibitory effects against <i>h</i>CA I, II, IV, and IX isoforms (<i>K</i>_<i>i</i> 8.5–833, 0.37–24.6, 44.2–777, and 27.3–32.1 nM, respectively). Furthermore, compounds <b>5e</b> and <b>5h</b> demonstrated a significant increase in glucose uptake in the rat hemidiaphragm experiment, outperforming pioglitazone. A robust PPARγ agonism in luciferase assay, full-length human PPARγ transactivation without artificially increasing its expression, and isothermal titration calorimetry for <i>K</i>_d determination were used to substantiate their PPARγ-dependent insulin-sensitizing activity. <i>In vivo</i> pharmacokinetic and tissue distribution experiments were carried out, revealing favorable properties. The <i>in vitro</i> activities were reflected into effective <i>in vivo</i> anti-inflammatory potential in the formalin-induced rat paw edema assay, and they also exhibited a favorable ulcerogenic profile. Furthermore, computational target prediction and network pharmacology analysis for the two most active molecules, <b>5e</b> and <b>5h</b>, identified important biological pathways associated with the intended outcomes. In this regard, <b>5e</b> and <b>5h</b> not only mitigated hyperglycemia and insulin resistance in an <i>in vivo</i> rat model of type 2 diabetes but also protected against renal and lipemic damage caused by metabolic dysfunction. Finally, docking simulations indicated potential binding interactions with the intended biological targets.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1627–1658 1627–1658"},"PeriodicalIF":4.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction.","authors":"Perihan A Elzahhar, Hisham A Nematalla, Malak A Abouayana, El Sayed H El Ashry, Mahmoud Balbaa, Andrea Petreni, Rasha Nassra, Hend A Yassin, Yasmine N Kamel, Mohamed A Elrewiny, Mahmoud A Agami, Monica Makkar, Minh Sai, Daniel Merk, Hala F Labib, Rosaria Spagnuolo, Marina Naldi, Manuela Bartolini, Soad A El-Hawash, Claudiu T Supuran, Ahmed S F Belal, Ahmed F El-Yazbi","doi":"10.1021/acsptsci.5c00011","DOIUrl":"10.1021/acsptsci.5c00011","url":null,"abstract":"<p><p>In light of the significant correlation between inflammatory alterations and metabolic dysfunction throughout different stages of metabolic disease progression, we focused on utilizing our previously characterized glitazone-derived anti-inflammatory 1,2,3-triazoles as lead compounds to create new multitarget directed ligands that interact with COX-2, peroxisome proliferator-activated receptor γ (PPARγ), and CA within the framework of metabolic disorders. Notably, seven compounds exhibited equivalent or similar COX-2 inhibitory effects to celecoxib. Four compounds, namely, <b>3b</b>, <b>3e</b>, <b>5e</b>, and <b>5h</b>, exhibited substantial nanomolar inhibitory effects against <i>h</i>CA I, II, IV, and IX isoforms (<i>K</i> _<i>i</i> 8.5-833, 0.37-24.6, 44.2-777, and 27.3-32.1 nM, respectively). Furthermore, compounds <b>5e</b> and <b>5h</b> demonstrated a significant increase in glucose uptake in the rat hemidiaphragm experiment, outperforming pioglitazone. A robust PPARγ agonism in luciferase assay, full-length human PPARγ transactivation without artificially increasing its expression, and isothermal titration calorimetry for <i>K</i> _d determination were used to substantiate their PPARγ-dependent insulin-sensitizing activity. <i>In vivo</i> pharmacokinetic and tissue distribution experiments were carried out, revealing favorable properties. The <i>in vitro</i> activities were reflected into effective <i>in vivo</i> anti-inflammatory potential in the formalin-induced rat paw edema assay, and they also exhibited a favorable ulcerogenic profile. Furthermore, computational target prediction and network pharmacology analysis for the two most active molecules, <b>5e</b> and <b>5h</b>, identified important biological pathways associated with the intended outcomes. In this regard, <b>5e</b> and <b>5h</b> not only mitigated hyperglycemia and insulin resistance in an <i>in vivo</i> rat model of type 2 diabetes but also protected against renal and lipemic damage caused by metabolic dysfunction. Finally, docking simulations indicated potential binding interactions with the intended biological targets.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1627-1658"},"PeriodicalIF":4.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}