Radiotracers provide molecular- and cellular-level information in a noninvasive manner and have become important tools for precision medicine. In particular, the successful clinical application of radioligand therapeutic (RLT) has further strengthened the role of nuclear medicine in clinical treatment. The complicated microenvironment of the lesion has rendered traditional single-targeted radiopharmaceuticals incapable of fully meeting the requirements. The design and development of dual-targeted and multitargeted radiopharmaceuticals have rapidly emerged. In recent years, significant progress has been made in the development of heterologous dual-targeted radiopharmaceuticals. This perspective aims to provide a comprehensive overview of the recent progress in these heterologous dual-targeted radiopharmaceuticals, with a special focus on the design of ligand structures, pharmacological properties, and preclinical and clinical evaluation. Furthermore, future directions are discussed from this perspective.
{"title":"Current Status and Perspectives of Novel Radiopharmaceuticals with Heterologous Dual-targeted Functions: 2013–2023","authors":"Zuojie Li, Qing Ruan, Yuhao Jiang, Qianna Wang, Guangxing Yin, Junhong Feng, Junbo Zhang","doi":"10.1021/acs.jmedchem.4c01608","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01608","url":null,"abstract":"Radiotracers provide molecular- and cellular-level information in a noninvasive manner and have become important tools for precision medicine. In particular, the successful clinical application of radioligand therapeutic (RLT) has further strengthened the role of nuclear medicine in clinical treatment. The complicated microenvironment of the lesion has rendered traditional single-targeted radiopharmaceuticals incapable of fully meeting the requirements. The design and development of dual-targeted and multitargeted radiopharmaceuticals have rapidly emerged. In recent years, significant progress has been made in the development of heterologous dual-targeted radiopharmaceuticals. This perspective aims to provide a comprehensive overview of the recent progress in these heterologous dual-targeted radiopharmaceuticals, with a special focus on the design of ligand structures, pharmacological properties, and preclinical and clinical evaluation. Furthermore, future directions are discussed from this perspective.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"4 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793806","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}
Pub Date : 2024-12-08DOI: 10.1021/acs.jmedchem.4c02392
Mohammed Monsoor Shaik, Samuel Pasco, Alessio Romerio, Carlo Pifferi, Silvia Sesana, Francesca Re, Charl Xavier Bezuidenhout, Silvia Bracco, Alberto Fernandez-Tejada, Juan Anguita, Francesco Peri
In this study, we formulated an alternative to AS01b by combining FP20, a synthetic TLR4 agonist, and QS21v, a minimal saponin adjuvant, aiming to improve the vaccine efficacy and stability. The phase transition temperature of FP20 was determined by using differential scanning calorimetry to be 43.9 °C, providing a foundation for the formulation process. The coformulation was prepared using a dry film method for even adjuvant distribution. Characterization by dynamic light scattering and nanoparticle tracking analysis revealed a uniform particle size distribution of ∼120 nm. Cryogenic electron microscopy (CryoEM) revealed nanosized interactions between FP20 and QS21v, forming stable structures that likely enhanced the antigen presentation and immune activation. These physicochemical properties contributed to a robust in vivo synergy, where the coformulation elicited significantly higher antigen-specific antibody titers compared to individual adjuvants. These findings suggest that the FP20+QS21v coformulation provides a potent, stable, and safer alternative to traditional adjuvants, enhancing both vaccine efficacy and immunogenicity.
{"title":"Development of a New Vaccine Adjuvant System Based on the Combination of the Synthetic TLR4 Agonist FP20 and a Synthetic QS-21 Variant","authors":"Mohammed Monsoor Shaik, Samuel Pasco, Alessio Romerio, Carlo Pifferi, Silvia Sesana, Francesca Re, Charl Xavier Bezuidenhout, Silvia Bracco, Alberto Fernandez-Tejada, Juan Anguita, Francesco Peri","doi":"10.1021/acs.jmedchem.4c02392","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02392","url":null,"abstract":"In this study, we formulated an alternative to AS01b by combining FP20, a synthetic TLR4 agonist, and QS21v, a minimal saponin adjuvant, aiming to improve the vaccine efficacy and stability. The phase transition temperature of FP20 was determined by using differential scanning calorimetry to be 43.9 °C, providing a foundation for the formulation process. The coformulation was prepared using a dry film method for even adjuvant distribution. Characterization by dynamic light scattering and nanoparticle tracking analysis revealed a uniform particle size distribution of ∼120 nm. Cryogenic electron microscopy (CryoEM) revealed nanosized interactions between FP20 and QS21v, forming stable structures that likely enhanced the antigen presentation and immune activation. These physicochemical properties contributed to a robust <i>in vivo</i> synergy, where the coformulation elicited significantly higher antigen-specific antibody titers compared to individual adjuvants. These findings suggest that the FP20+QS21v coformulation provides a potent, stable, and safer alternative to traditional adjuvants, enhancing both vaccine efficacy and immunogenicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789814","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}
Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure–activity relationship (SAR) studies led to the identification of compounds 27c and 33c as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC50 = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC50 > 200 μM in CEF cells; CC50 > 250 μM in MDCK cells). These findings highlight 27c and 33c as promising next-generation anti-influenza agents.
{"title":"Elaborate Structural Modifications Yielding Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles","authors":"Jiwei Zhang, Ruifang Jia, Huinan Jia, Ping Li, Yuanmin Jiang, Anna Bonomini, Chiara Bertagnin, Qiaojie Xu, Zhou Tan, Xiuli Ma, Arianna Loregian, Bing Huang, Xinyong Liu, Peng Zhan","doi":"10.1021/acs.jmedchem.4c02222","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02222","url":null,"abstract":"Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure–activity relationship (SAR) studies led to the identification of compounds <b>27c</b> and <b>33c</b> as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC<sub>50</sub> = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC<sub>50</sub> > 200 μM in CEF cells; CC<sub>50</sub> > 250 μM in MDCK cells). These findings highlight <b>27c</b> and <b>33c</b> as promising next-generation anti-influenza agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788447","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}
Pub Date : 2024-12-07DOI: 10.1021/acs.jmedchem.4c02401
Pan Chen, Yu Zou, Xiemin Wang, Zhichao Chen, Ke Dong, Jun Yang, Yaqian Cui, Jing Gu, Xinyi Wu, Xiaobo Li, Ying Zhou, Mi Guo, Zhiwei Zheng, Qi Chen, Weiwei Zhu, Di Wu, Lina Yin, Lingfeng Chen, Qin Ouyang, Guang Liang, Qidong Tang
Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (L7) through virtual screening and synthesized twenty-seven L7 derivatives. An optimal compound (A5) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2H-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer A5S showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. A5S had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, A5S showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, TJ-M2010-5, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors LM8.
{"title":"Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties","authors":"Pan Chen, Yu Zou, Xiemin Wang, Zhichao Chen, Ke Dong, Jun Yang, Yaqian Cui, Jing Gu, Xinyi Wu, Xiaobo Li, Ying Zhou, Mi Guo, Zhiwei Zheng, Qi Chen, Weiwei Zhu, Di Wu, Lina Yin, Lingfeng Chen, Qin Ouyang, Guang Liang, Qidong Tang","doi":"10.1021/acs.jmedchem.4c02401","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02401","url":null,"abstract":"Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (<b>L7</b>) through virtual screening and synthesized twenty-seven <b>L7</b> derivatives. An optimal compound (<b>A5</b>) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2<i>H</i>-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer <b>A5S</b> showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. <b>A5S</b> had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, <b>A5S</b> showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, <b>TJ-M2010-5</b>, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors <b>LM8</b>.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"82 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788481","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}
Pub Date : 2024-12-06DOI: 10.1021/acs.jmedchem.4c01995
Adeline Palisse, Tony Cheung, Aileen Blokhuis, Thomas Cogswell, Bruna S. Martins, Rick Riemens, Rick Schellekens, Giovanni Battocchio, Chimed Jansen, Matthew A. Cottee, Kimberly Ornell, Claudia Sacchetto, Leonardo Leon, Maaike van Hoek- Emmelot, Mark Bostock, Brooke Leann Brauer, Kevin Beaumont, Simon C. C. Lucas, Samiyah Ahmed, J. Henry Blackwell, Ulf Börjesson, Andrea Gohlke, Iva Monique T. Gramatikov, David Hargreaves, Vera van Hoeven, Vasudev Kantae, Lea Kupcova, Alexander G. Milbradt, Uthpala Seneviratne, Nancy Su, John Vales, Haiyun Wang, Michael J. White, Olaf Kinzel
BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 in vivo tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.22 This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h.
{"title":"Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors","authors":"Adeline Palisse, Tony Cheung, Aileen Blokhuis, Thomas Cogswell, Bruna S. Martins, Rick Riemens, Rick Schellekens, Giovanni Battocchio, Chimed Jansen, Matthew A. Cottee, Kimberly Ornell, Claudia Sacchetto, Leonardo Leon, Maaike van Hoek- Emmelot, Mark Bostock, Brooke Leann Brauer, Kevin Beaumont, Simon C. C. Lucas, Samiyah Ahmed, J. Henry Blackwell, Ulf Börjesson, Andrea Gohlke, Iva Monique T. Gramatikov, David Hargreaves, Vera van Hoeven, Vasudev Kantae, Lea Kupcova, Alexander G. Milbradt, Uthpala Seneviratne, Nancy Su, John Vales, Haiyun Wang, Michael J. White, Olaf Kinzel","doi":"10.1021/acs.jmedchem.4c01995","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01995","url":null,"abstract":"BFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 <i>in vivo</i> tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound <b>6</b>.<sup>22</sup> This work reports the structure-based optimization of compound <b>6</b> into a series of BFL1 inhibitors selective over the other BCL2 family members, with low <i>nanomolar</i> cellular activity when combined with AZD5991, exemplified by compound <b>20</b>. Compound <b>20</b> demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the <i>in vivo</i> study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound <b>20</b> stabilized the protein, extending the half-life to 10.8 h.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783022","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}
Elevated expression levels and enhanced activity of androgen receptor (AR) proteins are key factors in the development of androgenetic alopecia (AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown therapeutic potential, but their poor skin permeability requires invasive delivery methods. In this study, we conducted a structure feature analysis to investigate the effects of different linkers and E3 ligands of AR PROTACs on skin retention properties and degradation potency. Among these, compound C6 was discovered with excellent skin retention properties and nanomolar level AR degradation. By degrading AR, C6 regulated the expression levels of downstream paracrine factors associated with AGA. Additionally, after non-invasive topical application, C6 demonstrated excellent skin accumulation and achieved hair regeneration in an AGA mouse model. Overall, the development of non-invasive C6 offers a promising new strategy for AGA treatment and highlights the potential for using PROTACs in treating other skin diseases.
{"title":"Discovery of a Novel Non-invasive AR PROTAC Degrader for the Topical Treatment of Androgenetic Alopecia","authors":"Xinfei Mao, Weitong Hu, Mingfei Wu, Yuyuan Jin, Jingyi Zhao, Yihua Xu, Bizhi Li, Wentao Wang, Yiquan Wu, Jingyu Zhang, Ao Pang, Yuheng Jin, Tianyuan Zhang, Wenhai Huang, Jinxin Che, Jianqing Gao, Xiaowu Dong","doi":"10.1021/acs.jmedchem.4c02226","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02226","url":null,"abstract":"Elevated expression levels and enhanced activity of androgen receptor (AR) proteins are key factors in the development of androgenetic alopecia (AGA). AR proteolysis-targeting chimera (PROTAC) degraders have shown therapeutic potential, but their poor skin permeability requires invasive delivery methods. In this study, we conducted a structure feature analysis to investigate the effects of different linkers and E3 ligands of AR PROTACs on skin retention properties and degradation potency. Among these, compound <b>C6</b> was discovered with excellent skin retention properties and nanomolar level AR degradation. By degrading AR, <b>C6</b> regulated the expression levels of downstream paracrine factors associated with AGA. Additionally, after non-invasive topical application, <b>C6</b> demonstrated excellent skin accumulation and achieved hair regeneration in an AGA mouse model. Overall, the development of non-invasive <b>C6</b> offers a promising new strategy for AGA treatment and highlights the potential for using PROTACs in treating other skin diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782950","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}
Activation of the melanocortin 1 receptor (MC1R) mediates melanogenesis in melanocytes, anti-inflammatory effects in inflammatory cells, and antifibrotic effects in fibroblasts. Thus, MC1R agonists are expected to be beneficial for treating skin, autoimmune, inflammatory, and fibrotic diseases. Afamelanotide, an α-melanocyte-stimulating hormone (α-MSH) analogue MC1R agonist, is used clinically for treating erythropoietic protoporphyria (EPP) as a subcutaneous implant formulation. We explored nonpeptidic small-molecule MC1R agonists with the aim of identifying more convenient oral drugs. By exploring the structure of previously reported compound 5, we discovered compound 11 (MT-7117: dersimelagon phosphoric acid). This compound exhibited strong MC1R agonistic activity, good pharmacokinetic properties, and excellent safety profiles. Furthermore, compound 11 was effective in animal pigmentation evaluation and skin fibrosis model studies. Compound 11 is currently in clinical trials for the treatment of EPP, X-linked protoporphyria (XLP), and systemic sclerosis (SSc). Proof of concept was obtained in phase 2 clinical studies on EPP and XLP.
{"title":"Discovery of MT-7117 (Dersimelagon Phosphoric Acid): A Novel, Potent, Selective, and Nonpeptidic Orally Available Melanocortin 1 Receptor Agonist","authors":"Atsushi Sato, Kenji Morokuma, Takashi Adachi, Junki Andou, Masahiko Miyashiro, Tsuyoshi Suzuki, Yuko Kawano, Masahiro Kondo, Akihito Ogasawara, Mika Ide, Yasuo Yamamoto","doi":"10.1021/acs.jmedchem.4c02358","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02358","url":null,"abstract":"Activation of the melanocortin 1 receptor (MC1R) mediates melanogenesis in melanocytes, anti-inflammatory effects in inflammatory cells, and antifibrotic effects in fibroblasts. Thus, MC1R agonists are expected to be beneficial for treating skin, autoimmune, inflammatory, and fibrotic diseases. Afamelanotide, an α-melanocyte-stimulating hormone (α-MSH) analogue MC1R agonist, is used clinically for treating erythropoietic protoporphyria (EPP) as a subcutaneous implant formulation. We explored nonpeptidic small-molecule MC1R agonists with the aim of identifying more convenient oral drugs. By exploring the structure of previously reported compound <b>5</b>, we discovered compound <b>11</b> (MT-7117: dersimelagon phosphoric acid). This compound exhibited strong MC1R agonistic activity, good pharmacokinetic properties, and excellent safety profiles. Furthermore, compound <b>11</b> was effective in animal pigmentation evaluation and skin fibrosis model studies. Compound <b>11</b> is currently in clinical trials for the treatment of EPP, X-linked protoporphyria (XLP), and systemic sclerosis (SSc). Proof of concept was obtained in phase 2 clinical studies on EPP and XLP.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782999","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}
Pub Date : 2024-12-05DOI: 10.1021/acs.jmedchem.4c02139
Xinhua Liu, Dan Wang, Xiduan Wei, Dan Yang, Yao Ma, Gang Liu
Helicobacter pylori (H. pylori) infection is characterized by the complex interplay between H. pylori and gastric disorders. It has been established that NOD1 can be activated by the peptidoglycan (PGN) present in the cell wall of H. pylori, serving as a key mediator of inflammation and initiating the RIP2/NF-κB and MAPK inflammatory signaling pathways. In this article, we reported on the development of a 2-chloroquinazolin-4-ol derivative 66 as a potent and selective antagonist of both human and mouse NOD1, which effectively inhibited the expression of inflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL1, CXCL8) in immune and epithelial cells, as well as inflammatory cytokines (KC, IL-6) in a H. pylori-induced murine model of gastritis following oral administration. This study laid a foundation for treating gastritis induced by H. pylori infection.
{"title":"Selectively Antagonizing the NOD1-Mediated Inflammatory Signaling Pathway Mitigates the Gastric Inflammation Induced by Helicobacter pylori Infection","authors":"Xinhua Liu, Dan Wang, Xiduan Wei, Dan Yang, Yao Ma, Gang Liu","doi":"10.1021/acs.jmedchem.4c02139","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02139","url":null,"abstract":"<i>Helicobacter pylori</i> (<i>H. pylori</i>) infection is characterized by the complex interplay between <i>H. pylori</i> and gastric disorders. It has been established that NOD1 can be activated by the peptidoglycan (PGN) present in the cell wall of <i>H. pylori</i>, serving as a key mediator of inflammation and initiating the RIP2/NF-κB and MAPK inflammatory signaling pathways. In this article, we reported on the development of a 2-chloroquinazolin-4-ol derivative <b>66</b> as a potent and selective antagonist of both human and mouse NOD1, which effectively inhibited the expression of inflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL1, CXCL8) in immune and epithelial cells, as well as inflammatory cytokines (KC, IL-6) in a <i>H. pylori</i>-induced murine model of gastritis following oral administration. This study laid a foundation for treating gastritis induced by <i>H. pylori</i> infection.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"111 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783024","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}
Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor 10c, leading to compound 14b possessing great potency against PDE5A (IC50 = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of 14b (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor 14b which could serve as a potential candidate for treatment of PAH.
{"title":"Discovery and Optimization of Dihydroquinolin-2(1H)-ones as Novel Highly Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension","authors":"Bei Zhang, Zhong-Kai Zou, Jian-Fan Cai, Wen-Ming Tan, Jun-Wei Chen, Wei-En Li, Jing-Nan Liang, Wei-Pei Wu, Gang Wang, Xiao-Hong Ruan, Pei-Liang Zhao","doi":"10.1021/acs.jmedchem.4c02123","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02123","url":null,"abstract":"Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor <b>10c</b>, leading to compound <b>14b</b> possessing great potency against PDE5A (IC<sub>50</sub> = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of <b>14b</b> (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor <b>14b</b> which could serve as a potential candidate for treatment of PAH.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777208","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}
Pub Date : 2024-12-05DOI: 10.1021/acs.jmedchem.4c02039
Zifan Ye, Zhouye Xu, Jianhong Ouyang, Wenzhuang Shi, Shuangyu Li, Xu Wang, Binjuan Lu, Kang Wang, Yipeng Wang
Antimicrobial peptides (AMPs) are regarded as promising candidates for combating antimicrobial resistance. Previously we identified an AMP named Cm-CATH2 from the green sea turtle, which exhibited potent antibacterial activity and attractive potential in application. However, natural AMPs including Cm-CATH2 frequently suffer from structural instability and sensitivity to physiological conditions, limiting their effectiveness. Herein, we explored various strategies to enhance the efficacy and stability of Cm-CATH2, including peptide truncation, non-natural amino acid substitutions, disulfide bond-based cyclization, and stapled peptide techniques. The results demonstrated that the truncated NCM4 significantly improved the antimicrobial capability of Cm-CATH2 while also enhancing its anti-inflammatory and antibiofilm activities with minimal cytotoxicity. Further ornithine-substituted peptide oNCM markedly enhanced the stability of NCM4 without compromising its antimicrobial efficacy. This study successfully designed a lead peptide oNCM with significant development potential, while providing valuable insights into the advantages and limitations associated with diverse strategies for enhancing the stability of AMPs.
{"title":"Improving the Stability and Anti-Infective Activity of Sea Turtle AMPs Using Multiple Structural Modification Strategies","authors":"Zifan Ye, Zhouye Xu, Jianhong Ouyang, Wenzhuang Shi, Shuangyu Li, Xu Wang, Binjuan Lu, Kang Wang, Yipeng Wang","doi":"10.1021/acs.jmedchem.4c02039","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02039","url":null,"abstract":"Antimicrobial peptides (AMPs) are regarded as promising candidates for combating antimicrobial resistance. Previously we identified an AMP named <i>Cm</i>-CATH2 from the green sea turtle, which exhibited potent antibacterial activity and attractive potential in application. However, natural AMPs including <i>Cm</i>-CATH2 frequently suffer from structural instability and sensitivity to physiological conditions, limiting their effectiveness. Herein, we explored various strategies to enhance the efficacy and stability of <i>Cm</i>-CATH2, including peptide truncation, non-natural amino acid substitutions, disulfide bond-based cyclization, and stapled peptide techniques. The results demonstrated that the truncated NCM4 significantly improved the antimicrobial capability of <i>Cm</i>-CATH2 while also enhancing its anti-inflammatory and antibiofilm activities with minimal cytotoxicity. Further ornithine-substituted peptide oNCM markedly enhanced the stability of NCM4 without compromising its antimicrobial efficacy. This study successfully designed a lead peptide oNCM with significant development potential, while providing valuable insights into the advantages and limitations associated with diverse strategies for enhancing the stability of AMPs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777049","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}
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