ACS Pharmacology & Translational Science最新文献_第6页

Emerging Landscape of In Vitro Models for Assessing Rheumatoid Arthritis Management 用于评估类风湿性关节炎管理的体外模型的新格局

ACS Pharmacology & Translational Science Pub Date : 2024-07-18 DOI: 10.1021/acsptsci.4c00260

Abhay Prakash Mishra, Rajesh Kumar, Seetha Harilal, Manisha Nigam, Deepanjan Datta, Sudarshan Singh

{"title":"Emerging Landscape of In Vitro Models for Assessing Rheumatoid Arthritis Management","authors":"Abhay Prakash Mishra, Rajesh Kumar, Seetha Harilal, Manisha Nigam, Deepanjan Datta, Sudarshan Singh","doi":"10.1021/acsptsci.4c00260","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00260","url":null,"abstract":"Rheumatoid arthritis (RA) is a complex condition that is influenced by various causes, including immunological, genetic, and environmental factors. Several studies using animal models have documented immune system dysfunction and described the clinical characteristics of the disease. These studies have provided valuable insights into the pathogenesis of inflammatory arthritis and the identification of new targets for treatment. Nevertheless, none of these animal models successfully replicated all the characteristics of RA. Additionally, numerous experimental medications, which were developed based on our enhanced comprehension of the immune system’s function in RA, have shown potential in animal research but ultimately proved ineffective during different stages of clinical trials. There have been several novel therapy alternatives, which do not achieve a consistently outstanding therapeutic outcome in all patients. This underscores the importance of employing the progress in in vitro models, particularly 3D models like tissue explants, and diverse multicomponent approaches such as coculture strategies, synovial membrane, articular cartilage, and subchondral bone models that accurately replicate the structural characteristics of RA pathophysiology. These methods are crucial for the advancement of potential therapeutic strategies. This review discusses the latest advancements in in vitro models and their potential to greatly impact research on managing RA.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753873","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}

引用次数: 0

In-Depth Characterization for Methionine Oxidization in Complementary Domain Region by Hydrophobic Interaction Chromatography 利用疏水相互作用色谱法深入表征互补结构域中的蛋氨酸氧化作用

ACS Pharmacology & Translational Science Pub Date : 2024-07-18 DOI: 10.1021/acsptsci.4c00296

Liu Tang, Huiliang Geng, Lei Zhang, Xinyi Wang, Mengdan Fei, Boyuan Yang, Haijie Sun, Zhongli Zhang

{"title":"In-Depth Characterization for Methionine Oxidization in Complementary Domain Region by Hydrophobic Interaction Chromatography","authors":"Liu Tang, Huiliang Geng, Lei Zhang, Xinyi Wang, Mengdan Fei, Boyuan Yang, Haijie Sun, Zhongli Zhang","doi":"10.1021/acsptsci.4c00296","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00296","url":null,"abstract":"The oxidation of the complementarity-determining region (CDR) in monoclonal antibodies (mAbs) is a critical quality attribute that can affect the clinical efficacy and safety of recombinant mAb therapeutics. In this study, a robust hydrophobic interaction chromatography (HIC) method was developed to quantify and characterize CDR oxidation variants in mAb-A by using a Proteomix Butyl-NP5 column. The HIC analysis revealed oxidation variants that eluted earlier than the main species with weaker hydrophobicity. It was found that Met105 in the CDR was more susceptible to oxidation. Additionally, it was noted that the oxidation of Met105 on a single heavy chain resulted in elution at a distinct position compared to the oxidation on two heavy chains. This observation led to the fractionation and enrichment of the oxidized variants for further evaluation of their biofunction. The study also demonstrated that the oxidation of Met105 did not impact the antigen-binding capacity but significantly reduced the PD-1/PD-L1 blockade activity of mAb-A. The HIC method, which was employed to quantify CDR oxidation, underwent validation and was subsequently utilized for stability studies as well as for assessing the similarity between mAb-A and its reference product.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141785272","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}

引用次数: 0

Preclinical Evaluation of Sigma 1 Receptor Antagonists as a Novel Treatment for Painful Diabetic Neuropathy 将 Sigma 1 受体拮抗剂作为糖尿病痛性神经病变的新型疗法的临床前评估

ACS Pharmacology & Translational Science Pub Date : 2024-07-18 DOI: 10.1021/acsptsci.4c00186

Youyi Peng, Allen H. Zhang, Liping Wei, William J. Welsh

{"title":"Preclinical Evaluation of Sigma 1 Receptor Antagonists as a Novel Treatment for Painful Diabetic Neuropathy","authors":"Youyi Peng, Allen H. Zhang, Liping Wei, William J. Welsh","doi":"10.1021/acsptsci.4c00186","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00186","url":null,"abstract":"The global prevalence of diabetes is steadily rising, with an estimated 537 million adults affected by diabetes in 2021, projected to reach 783 million by 2045. A severe consequence of diabetes is the development of painful diabetic neuropathy (PDN), afflicting approximately one in every three diabetic patients and significantly compromising their quality of life. Current pharmacotherapies for PDN provide inadequate pain relief for many patients, underscoring the need for novel treatments that are both safe and effective. The Sigma 1 Receptor (S1R) is a ligand-operated chaperone protein that resides at the mitochondria-associated membrane of the endoplasmic reticulum. The S1R has been shown to play crucial roles in regulating cellular processes implicated in pain modulation. This study explores the potential of PW507, a novel S1R antagonist, as a therapeutic candidate for PDN. PW507 exhibited promising in vitro and in vivo properties in terms of ADME, toxicity, pharmacokinetics, and safety. In preclinical rat models of Streptozotocin-induced diabetic neuropathy, PW507 demonstrated significant efficacy in alleviating mechanical allodynia and thermal hyperalgesia following both acute and chronic (2-week) administration, without inducing tolerance and visual evidence of toxicity. To the best of our knowledge, this is the first report to evaluate an S1R antagonist in STZ-induced diabetic rats following both acute and 2-week chronic administration, offering compelling preclinical evidence for the potential use of PW507 as a promising therapeutic option for PDN.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753874","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}

引用次数: 0

Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model 伊维菌素在三阴性乳腺癌小鼠模型中与调制电热疗法协同作用并提高其抗癌效果

ACS Pharmacology & Translational Science Pub Date : 2024-07-17 DOI: 10.1021/acsptsci.4c00314

Kenan Aloss, Pedro Henrique Leroy Viana, Syeda Mahak Zahra Bokhari, Nino Giunashvili, Csaba András Schvarcz, Dániel Bócsi, Zoltán Koós, Zoltán Benyó, Péter Hamar

{"title":"Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model","authors":"Kenan Aloss, Pedro Henrique Leroy Viana, Syeda Mahak Zahra Bokhari, Nino Giunashvili, Csaba András Schvarcz, Dániel Bócsi, Zoltán Koós, Zoltán Benyó, Péter Hamar","doi":"10.1021/acsptsci.4c00314","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00314","url":null,"abstract":"Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719932","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}

引用次数: 0

Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies 间充质干细胞衰老机制的新动向及其对治疗策略的影响

ACS Pharmacology & Translational Science Pub Date : 2024-07-17 DOI: 10.1021/acsptsci.4c00284

Jing Wang, Muqing Zhang, Hu Wang

{"title":"Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies","authors":"Jing Wang, Muqing Zhang, Hu Wang","doi":"10.1021/acsptsci.4c00284","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00284","url":null,"abstract":"Mesenchymal stem cells (MSCs) hold significant promise for regenerative medicine and tissue engineering due to their unique multipotent differentiation ability and immunomodulatory properties. MSC therapy is widely discussed and utilized in clinical treatment. However, during both in vitro expansion and in vivo transplantation, MSCs are prone to senescence, an irreversible growth arrest characterized by morphological, gene expression, and functional changes in genomic regulation. The microenvironment surrounding MSCs plays a crucial role in modulating their senescence phenotype, influenced by factors such as hypoxia, inflammation, and aging status. Numerous strategies targeting MSC senescence have been developed, including senolytics and senomorphic agents, antioxidant and exosome therapies, mitochondrial transfer, and niche modulation. Novel approaches addressing replicative senescence have also emerged. This paper comprehensively reviews the current molecular manifestations of MSC senescence, addresses the environmental impact on senescence, and highlights potential therapeutic strategies to mitigate senescence in MSC-based therapies. These insights aim to enhance the efficacy and understanding of MSC therapies.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719931","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}

引用次数: 0

Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration 芳香胺 N-乙酰转移酶 1 的小分子抑制剂可减轻细胞呼吸作用

ACS Pharmacology & Translational Science Pub Date : 2024-07-17 DOI: 10.1021/acsptsci.4c00282

Chandra Choudhury, James E. Egleton, Neville J. Butcher, Angela J. Russell, Rodney F. Minchin

引用次数: 0

Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling of Nanomaterials 基于生理学的纳米材料药物代谢动力学 (PBPK) 建模进展

ACS Pharmacology & Translational Science Pub Date : 2024-07-11 DOI: 10.1021/acsptsci.4c00250

Ozlem Ozbek, Destina Ekingen Genc, Kutlu O. Ulgen

{"title":"Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling of Nanomaterials","authors":"Ozlem Ozbek, Destina Ekingen Genc, Kutlu O. Ulgen","doi":"10.1021/acsptsci.4c00250","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00250","url":null,"abstract":"Nanoparticles (NPs) have been widely used to improve the pharmacokinetic properties and tissue distribution of small molecules such as targeting to a specific tissue of interest, enhancing their systemic circulation, and enlarging their therapeutic properties. NPs have unique and complicated in vivo disposition properties compared to small molecule drugs due to their complex multifunctionality. Physiologically based pharmacokinetic (PBPK) modeling has been a powerful tool in the simulation of the absorption, distribution, metabolism, and elimination (ADME) characteristics of the materials, and it can be used in the characterization and prediction of the systemic disposition, toxicity, efficacy, and target exposure of various types of nanoparticles. In this review, recent advances in PBPK model applications related to the nanoparticles with unique properties, and dispositional features in the biological systems, ADME characteristics, the description of transport processes of nanoparticles in the PBPK model, and the challenges in PBPK model development of nanoparticles are delineated and juxtaposed with those encountered in small molecule models. Nanoparticle related, non-nanoparticle-related, and interspecies-scaling methods applied in PBPK modeling are reviewed. In vitro to in vivo extrapolation (IVIVE) methods being a promising computational tool to provide in vivo predictions from the results of in vitro and in silico studies are discussed. Finally, as a recent advancement ML/AI-based approaches and challenges in PBPK modeling in the estimation of ADME parameters and pharmacokinetic (PK) analysis results are introduced.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609471","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}

引用次数: 0

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2 基于 11C 标记的异吲哚酮正异位调节剂的放射合成与评估，用于对代谢谷氨酸受体 2 进行正电子发射断层扫描成像

ACS Pharmacology & Translational Science Pub Date : 2024-07-10 DOI: 10.1021/acsptsci.4c00261

Yinlong Li, Kenneth Dahl, Peter Johnström, Katarina Varnäs, Lars Farde, Christer Halldin, Amy Medd, Donna Maier, Mark E. Powell, Jiahui Chen, Richard Van, Jimmy Patel, Ahmad Chaudhary, Yabiao Gao, Zhendong Song, Ahmed Haider, Yihan Shao, Charles S. Elmore, Steven Liang, Magnus Schou

{"title":"Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2","authors":"Yinlong Li, Kenneth Dahl, Peter Johnström, Katarina Varnäs, Lars Farde, Christer Halldin, Amy Medd, Donna Maier, Mark E. Powell, Jiahui Chen, Richard Van, Jimmy Patel, Ahmad Chaudhary, Yabiao Gao, Zhendong Song, Ahmed Haider, Yihan Shao, Charles S. Elmore, Steven Liang, Magnus Schou","doi":"10.1021/acsptsci.4c00261","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00261","url":null,"abstract":"The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (Ki mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614428","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}

引用次数: 0

Mass Spectrometry Imaging Reveals Region-Specific Lipid Alterations in the Mouse Brain in Response to Efavirenz Treatment 质谱成像揭示小鼠脑内特定区域脂质变化对依非韦伦治疗的反应

ACS Pharmacology & Translational Science Pub Date : 2024-07-09 DOI: 10.1021/acsptsci.4c00228

Nav Raj Phulara, Apurv Rege, Charles J. Bieberich, Herana Kamal Seneviratne

{"title":"Mass Spectrometry Imaging Reveals Region-Specific Lipid Alterations in the Mouse Brain in Response to Efavirenz Treatment","authors":"Nav Raj Phulara, Apurv Rege, Charles J. Bieberich, Herana Kamal Seneviratne","doi":"10.1021/acsptsci.4c00228","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00228","url":null,"abstract":"Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609473","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}

引用次数: 0

A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for In Vivo Studies 一种用于体内研究的高效力、口服生物可用吡唑衍生大麻素 CB2 受体选择性全激动剂

ACS Pharmacology & Translational Science Pub Date : 2024-07-08 DOI: 10.1021/acsptsci.4c00269

Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch

{"title":"A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for In Vivo Studies","authors":"Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch","doi":"10.1021/acsptsci.4c00269","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00269","url":null,"abstract":"The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation in vivo, optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for in vivo studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency (Ki 0.13–1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein-mediated efflux from the brain. 3H and 14C labeled RNB-61 showed apparent Kd values of <4 nM toward human CB2R in both cell and tissue experiments. The 6,800-fold selectivity over CB1 receptors and negligible off-targets in vitro, combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical in vivo studies with superior biophysical and PK properties over generally used CB2R ligands.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609472","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}

引用次数: 0