Journal of Medicinal Chemistry最新文献

Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent. 解决胃酸还原剂导致的弱碱性 TYK2 抑制剂口服吸收障碍的原药策略

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI: 10.1021/acs.jmedchem.4c02219

Murugaiah A M Subbaiah, Thangeswaran Ramar, Maheswara Reddy, Sankara Sivaprasad Lvj, Shekhar Yeshwante, Srikanth Sridhar, Salil Desai, Manoj Chiney, Elizabeth A Dierks, Arvind Mathur, Ryan Moslin, David S Weinstein

{"title":"Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent.","authors":"Murugaiah A M Subbaiah, Thangeswaran Ramar, Maheswara Reddy, Sankara Sivaprasad Lvj, Shekhar Yeshwante, Srikanth Sridhar, Salil Desai, Manoj Chiney, Elizabeth A Dierks, Arvind Mathur, Ryan Moslin, David S Weinstein","doi":"10.1021/acs.jmedchem.4c02219","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02219","url":null,"abstract":"The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and Cmax between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103. NMDA 受体靶向抗抑郁药的研究进展：从发现 d-Cycloserine 到 Lu AF90103 的临床前疗效。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI: 10.1021/acs.jmedchem.4c01477

Erhad Ascic, Mauro Marigo, Laurent David, Kjartan Frisch Herrik, Morten Grupe, Charlotte Hougaard, Arne Mørk, Christopher R Jones, Lassina Badolo, Kristen Frederiksen, Harrie C M Boonen, Henrik Sindal Jensen, John Paul Kilburn

{"title":"Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103.","authors":"Erhad Ascic, Mauro Marigo, Laurent David, Kjartan Frisch Herrik, Morten Grupe, Charlotte Hougaard, Arne Mørk, Christopher R Jones, Lassina Badolo, Kristen Frederiksen, Harrie C M Boonen, Henrik Sindal Jensen, John Paul Kilburn","doi":"10.1021/acs.jmedchem.4c01477","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01477","url":null,"abstract":"The discovery of d-cycloserine (DCS), a partial agonist of the NMDA receptor that exhibits antidepressant effects without the psychotomimetic effects of ketamine, has fueled interest in new NMDA-targeting antidepressants. Our objective was to identify potent partial agonists mirroring DCS, particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound 42d. This compound acts as a partial agonist of the GluN1/GluN2B complex, exhibiting 24% efficacy, and has an EC50 value of 78 nM. Subsequent investigations led us to 42e (Lu AF90103), a methyl ester prodrug of 42d capable of penetrating the blood-brain barrier, as confirmed by rat microdialysis studies. In different rat in vivo models relevant to neuropsychiatric diseases, administering 42e led to 42d demonstrating both acute effects, observed in a seizure model and EEG, and lasting effects in the stress-sensitive hippocampal pathway and an antidepressant-sensitive model.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948. 发现首个支链酮酸脱氢酶（BDK）抑制剂临床候选药物 PF-07328948。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-19 DOI: 10.1021/acs.jmedchem.4c02230

Kevin J Filipski, Luis A Martinez-Alsina, Matthew R Reese, Edelweiss Evrard, Leanne M Buzon, Kimberly O Cameron, Yuan Zhang, Karen J Coffman, James Bradow, Bethany L Kormos, Shenping Liu, John D Knafels, Parag V Sahasrabudhe, Jie Chen, Amit S Kalgutkar, Andrew J Bessire, Christine C Orozco, Amanda Balesano, Matthew A Cerny, Eliza Bollinger, Allan R Reyes, Brigitte Laforest, Amy Rosado, George Williams, Mackenzie Marshall, Kelly Tam Neale, Xian Chen, Dinesh Hirenallur-Shanthappa, John C Stansfield, John Groarke, Ruolun Qiu, Spinel Karas, Rachel J Roth Flach, William P Esler

{"title":"Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.","authors":"Kevin J Filipski, Luis A Martinez-Alsina, Matthew R Reese, Edelweiss Evrard, Leanne M Buzon, Kimberly O Cameron, Yuan Zhang, Karen J Coffman, James Bradow, Bethany L Kormos, Shenping Liu, John D Knafels, Parag V Sahasrabudhe, Jie Chen, Amit S Kalgutkar, Andrew J Bessire, Christine C Orozco, Amanda Balesano, Matthew A Cerny, Eliza Bollinger, Allan R Reyes, Brigitte Laforest, Amy Rosado, George Williams, Mackenzie Marshall, Kelly Tam Neale, Xian Chen, Dinesh Hirenallur-Shanthappa, John C Stansfield, John Groarke, Ruolun Qiu, Spinel Karas, Rachel J Roth Flach, William P Esler","doi":"10.1021/acs.jmedchem.4c02230","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02230","url":null,"abstract":"Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Opportunities and Challenges of Arginase Inhibitors in Cancer: A Medicinal Chemistry Perspective. 癌症中精氨酸酶抑制剂的机遇与挑战：药物化学的视角。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1021/acs.jmedchem.4c01429

Mariacristina Failla, Maria Cristina Molaro, Marica Erminia Schiano, Marta Serafini, Gioele Antonio Tiburtini, Eleonora Gianquinto, Riccardo Scoccia, Chiara Battisegola, Maria Grazia Rimoli, Konstantin Chegaev, Giuseppe Ercolano, Loretta Lazzarato, Francesca Spyrakis, Federica Sodano

{"title":"Opportunities and Challenges of Arginase Inhibitors in Cancer: A Medicinal Chemistry Perspective.","authors":"Mariacristina Failla, Maria Cristina Molaro, Marica Erminia Schiano, Marta Serafini, Gioele Antonio Tiburtini, Eleonora Gianquinto, Riccardo Scoccia, Chiara Battisegola, Maria Grazia Rimoli, Konstantin Chegaev, Giuseppe Ercolano, Loretta Lazzarato, Francesca Spyrakis, Federica Sodano","doi":"10.1021/acs.jmedchem.4c01429","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01429","url":null,"abstract":"The overexpression of two arginase (ARG) isoforms, ARG1 and ARG2, contributes to the onset of numerous disorders, including cardiovascular and immune-mediated diseases, as well as tumors. To elucidate the specific roles of ARG1 and ARG2 without interfering with their physiological functions, it is crucial to develop effective ARG inhibitors that target only one isoform, while maintaining low toxicity and an adequate pharmacokinetic profile. In this context, we present a comprehensive overview of the different generations of ARG inhibitors. Given the general lack of selectivity in most existing inhibitors, we analyzed the structural features and plasticity of the ARG1 and ARG2 binding sites to explore the potential for designing inhibitors with novel binding patterns. We also review ongoing preclinical and clinical studies on selected inhibitors, highlighting both progress and challenges in developing potent, selective ARG inhibitors. Furthermore, we discuss medicinal chemistry strategies that may accelerate the discovery of selective ARG inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

De Novo Discovery of a Noncovalent Cell-Penetrating Bicyclic Peptide Inhibitor Targeting SARS-CoV-2 Main Protease. 针对 SARS-CoV-2 主要蛋白酶的非共价细胞穿透性双环肽抑制剂的新发现

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1021/acs.jmedchem.4c01639

Yahong Tan, Jinyue Yang, Min Wang, Qi Peng, Yongqi Li, Lifeng Fu, Mengmeng Zhang, Jiang Wu, Guanya Yang, Christopher John Hipolito, Youming Zhang, Jianxun Qi, Yi Shi, Yizhen Yin

{"title":"De Novo Discovery of a Noncovalent Cell-Penetrating Bicyclic Peptide Inhibitor Targeting SARS-CoV-2 Main Protease.","authors":"Yahong Tan, Jinyue Yang, Min Wang, Qi Peng, Yongqi Li, Lifeng Fu, Mengmeng Zhang, Jiang Wu, Guanya Yang, Christopher John Hipolito, Youming Zhang, Jianxun Qi, Yi Shi, Yizhen Yin","doi":"10.1021/acs.jmedchem.4c01639","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01639","url":null,"abstract":"Macrocyclic peptides have garnered significant attention as promising drug candidates. However, they typically face challenges in achieving and enhancing cell permeability for access to intracellular targets. In this study, we focused on the de novo screening of macrocyclic peptide inhibitors against the main protease (Mpro) of SARS-CoV-2 and identified novel noncovalently bound macrocyclic peptides that effectively inhibit proteolytic activity. High-resolution crystal structures further revealed molecular interactions between the macrocyclic peptides and Mpro. Subsequently, a specific macrocyclic peptide lacking cell permeability was further optimized and transformed into a low-toxicity, metabolically stable bicyclic peptide with a cell penetration capacity and therapeutic potential against SARS-CoV-2. The bicyclic peptide was achieved using a novel strategy that involved introducing both a bicyclic structure and a bridging perfluorobiphenyl group. Our study not only provides a lead peptide inhibitor for COVID-19 but also offers valuable insights into achieving cell penetration for macrocyclic peptides through strategic modifications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to "Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis". 对 "发现一种可阻止 NLRP3 炎症小体激活和裂解的 Pro-Caspase-1 酶原共价抑制剂 "的更正。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-18 DOI: 10.1021/acs.jmedchem.4c02771

Dongyi Cao, Ruiying Xi, Hongye Li, Zhonghui Zhang, Xiaoke Shi, Shanshan Li, Yujie Jin, Wanli Liu, Guolin Zhang, Xiaohua Liu, Shunxi Dong, Xiaoming Feng, Fei Wang

引用次数: 0

4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells. 4-(吡唑基)苯磺酰胺脲类作为大肠癌细胞的碳酸酐酶抑制剂和缺氧介导的化疗增敏剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI: 10.1021/acs.jmedchem.4c01894

Wagdy M Eldehna, Mohamed Fares, Alessandro Bonardi, Moscos Avgenikos, Fady Baselious, Matthias Schmidt, Tarfah Al-Warhi, Hatem A Abdel-Aziz, Robert Rennert, Thomas S Peat, Claudiu T Supuran, Ludger A Wessjohann, Hany S Ibrahim

{"title":"4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells.","authors":"Wagdy M Eldehna, Mohamed Fares, Alessandro Bonardi, Moscos Avgenikos, Fady Baselious, Matthias Schmidt, Tarfah Al-Warhi, Hatem A Abdel-Aziz, Robert Rennert, Thomas S Peat, Claudiu T Supuran, Ludger A Wessjohann, Hany S Ibrahim","doi":"10.1021/acs.jmedchem.4c01894","DOIUrl":"10.1021/acs.jmedchem.4c01894","url":null,"abstract":"Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (hCA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas (SH7a-t) were developed and evaluated for their inhibitory activity against hCA IX and XII. They showed promising results (hCA IX: KI = 15.9-67.6 nM, hCA XII: KI = 16.7-65.7 nM). Particularly, SH7s demonstrated outstanding activity (KIs = 15.9 nM for hCA IX and 55.2 nM for hCA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, SH7s exhibited broad-spectrum activity with an effective growth inhibition full panel GI50 (MG-MID) value of 3.5 μM and a subpanel GI50 (MG-MID) range of 2.4-6.3 μM. Furthermore, SH7s enhanced the efficacy of Taxol and 5-fluorouracil in cotreatment regimens under hypoxic conditions in HCT-116 colorectal cancer cells, indicating its potential as a promising anticancer agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer. 以 Sigma-2 受体 (S2R) 为靶点的第一类硫代氨基甲酸盐金属复合物，作为抗击胰腺癌的创新策略。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-17 DOI: 10.1021/acs.jmedchem.4c01410

Alessandra Barbanente, Joanna Kopecka, Daniele Vitone, Mauro Niso, Rosanna Rizzi, Corrado Cuocci, Francesca Serena Abatematteo, Francesco Mastropasqua, Nicola Antonio Colabufo, Nicola Margiotta, Fabio Arnesano, Chiara Riganti, Carmen Abate

{"title":"First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer.","authors":"Alessandra Barbanente, Joanna Kopecka, Daniele Vitone, Mauro Niso, Rosanna Rizzi, Corrado Cuocci, Francesca Serena Abatematteo, Francesco Mastropasqua, Nicola Antonio Colabufo, Nicola Margiotta, Fabio Arnesano, Chiara Riganti, Carmen Abate","doi":"10.1021/acs.jmedchem.4c01410","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01410","url":null,"abstract":"Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs). FA4 has shown potent activity against pancreatic cancer in vivo. We synthesized complexes of FA4 with Cu(II) and Pt(II), and compared their efficacy with complexes of the non-S2R-targeting TSC 1. TSC-Cu exhibited over 50-fold higher in vitro cytotoxicity than TSCs-Pt, which was less active than TSCs. FA4-Cu induced apoptotic cell death via ER and mitochondrial stress showing more potent activity than FA4. This in vitro effect was replicated in the preclinical PANC-1 model, where FA4-Cu was more potent than FA4, 1, and 1-Cu. These results support further exploration of FA4-Cu as a potential therapy for pancreatic cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Phenotypic High-Throughput Screen Identifies Small Molecule Modulators of Endogenous RGS10 in BV-2 Cells. 表型高通量筛选确定了 BV-2 细胞中内源性 RGS10 的小分子调节剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI: 10.1021/acs.jmedchem.4c01738

Shwetal Talele, Stephanie Gonzalez, Julia Trudeau, Ahmad Junaid, Cody A Loy, Ryan A Altman, Benita Sjögren

{"title":"A Phenotypic High-Throughput Screen Identifies Small Molecule Modulators of Endogenous RGS10 in BV-2 Cells.","authors":"Shwetal Talele, Stephanie Gonzalez, Julia Trudeau, Ahmad Junaid, Cody A Loy, Ryan A Altman, Benita Sjögren","doi":"10.1021/acs.jmedchem.4c01738","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01738","url":null,"abstract":"Chronic dysregulation of microglial phenotypic balance contributes to prolonged neuroinflammation and neurotoxicity, which is a hallmark of neurodegenerative diseases. Thus, targeting microglial inflammatory signaling represents a promising therapeutic strategy for neurodegenerative diseases. Regulator of G protein Signaling 10 (RGS10) is highly expressed in microglia, where it suppresses pro-inflammatory signaling. However, RGS10 is silenced following microglial activation, augmenting inflammatory responses. While modulating RGS10 expression is a promising strategy to suppress pro-inflammatory microglial activation, no chemical tools with this ability exist. We developed a phenotypic high-throughput assay to screen for compounds with the ability to reverse interferon-γ (IFNγ)-induced RGS10 silencing in BV-2 cells. Identified hits had no effect on RGS10 expression in the absence of stimulus or in response to lipopolysaccharide (LPS). Furthermore, the hits reversed some of the inflammatory gene expression induced by IFNγ. This is the first demonstration of the potential for small molecule intervention to modulate the RGS10 expression in microglia.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket. 通过靶向金属袋发现具有抗肺纤维化作用的选择性 PDE1 抑制剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI: 10.1021/acs.jmedchem.4c01533

Mei-Yan Jiang, Chen Zhang, Qing-Hua Huang, Ling-Ling Feng, Yi-Yi Yang, Qian Zhou, Hai-Bin Luo, Yinuo Wu

引用次数: 0