Albumin-binding prodrugs have been explored to overcome the limitations of small-molecule anticancer chemotherapy agents, such as inadequate physiological and pharmaceutical compatibility, as well as rapid renal clearance. Herein, we investigated two endogenous albumin-binding prodrugs, M-g-SN38 and S-g-SN38, forming macromolecular conjugates. Both prodrugs exhibited robust stability in murine and human plasma, crucial for their therapeutic potential. Selective activation by β-glucuronidase ensures minimal toxicity in their inactive state. Notably, M-g-SN38 exhibited higher cellular uptake, a longer circulation half-life, and enhanced tumor accumulation compared to S-g-SN38, suggesting its greater potential for improved antitumor efficacy. In vivo, M-g-SN38 exhibited significant antitumor activity, leading to profound tumor reduction and, in many cases, marked depletion and complete eradication in all treated mice in the HCT116 xenograft model. Furthermore, M-g-SN38 also demonstrated pronounced antitumor efficacy in the BxPC-3 xenograft model. Together, these findings provide new insights for the development of albumin-binding prodrugs.
{"title":"Comparative Study on Covalent and Noncovalent Endogenous Albumin-Binding β-Glucuronidase-Activated SN38 Prodrugs for Antitumor Efficacy","authors":"Yingxin Lu, Xing Jiang, Biyu Yang, Mengyuan Ding, Yanyan Shen, Jiyu Jin, Jiahui Yu, Wei Lu, Yi Chen, Shulei Zhu","doi":"10.1021/acs.jmedchem.4c03096","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03096","url":null,"abstract":"Albumin-binding prodrugs have been explored to overcome the limitations of small-molecule anticancer chemotherapy agents, such as inadequate physiological and pharmaceutical compatibility, as well as rapid renal clearance. Herein, we investigated two endogenous albumin-binding prodrugs, <b>M-g-SN38</b> and <b>S-g-SN38</b>, forming macromolecular conjugates. Both prodrugs exhibited robust stability in murine and human plasma, crucial for their therapeutic potential. Selective activation by β-glucuronidase ensures minimal toxicity in their inactive state. Notably, <b>M-g-SN38</b> exhibited higher cellular uptake, a longer circulation half-life, and enhanced tumor accumulation compared to <b>S-g-SN38</b>, suggesting its greater potential for improved antitumor efficacy. In vivo, <b>M-g-SN38</b> exhibited significant antitumor activity, leading to profound tumor reduction and, in many cases, marked depletion and complete eradication in all treated mice in the HCT116 xenograft model. Furthermore, <b>M-g-SN38</b> also demonstrated pronounced antitumor efficacy in the BxPC-3 xenograft model. Together, these findings provide new insights for the development of albumin-binding prodrugs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"59 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790071","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 : 2025-04-05DOI: 10.1021/acs.jmedchem.5c00202
Kun Zhang, Tianhao Xing, Li Ding, Christophe Pannecouque, Erik De Clercq, Angela Corona, Laura Dettori, Enzo Tramontano, Shuai Wang, Fen-Er Chen
Deuteration strategy holds significant importance in the field of drug development. In this study, the deuteration strategy was applied to incorporate deuterated methyl groups at the metabolic sites where methyl groups were originally present, with the expectation of improving the anti-HIV activity, safety, and druggability. Among the deuterated compounds, the exemplary compound 5a (ZK-316) exhibited potent and broad-spectrum activity against wild-type and clinically observed mutant strains, with EC50 values ranging from 0.99 to 75.1 nM, surpassing that of the hit compound 3 (EC50 = 1.86–795.76 nM). Moreover, low cytotoxicity was exhibited by ZK-316 (CC50 > 225 nM), which was over 36.8 times lower than that of compound 3, and high selectivity was also shown. Not only was there no apparent inhibition of cytochrome P450 (CYP) enzymes, but also low human ether-à-go-go-related gene (hERG) toxicity was found. And favorable pharmacokinetic profiles were shown as well, with a bioavailability of 29%, all of which indicated its promising druggability. Additionally, the identification of the metabolites of ZK-316 was carried out to verify the stability of the deuterated methyl groups within human liver microsomes. These results offer valuable insights into the development of deuterated non-nucleoside reverse transcriptase inhibitors (NNRTIs) for human immunodeficiency virus (HIV) therapy.
{"title":"Deuteration Strategy-Inspired Design of Novel Diarylpyrimidine Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Improved Efficacy, Selectivity, and Druggability","authors":"Kun Zhang, Tianhao Xing, Li Ding, Christophe Pannecouque, Erik De Clercq, Angela Corona, Laura Dettori, Enzo Tramontano, Shuai Wang, Fen-Er Chen","doi":"10.1021/acs.jmedchem.5c00202","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00202","url":null,"abstract":"Deuteration strategy holds significant importance in the field of drug development. In this study, the deuteration strategy was applied to incorporate deuterated methyl groups at the metabolic sites where methyl groups were originally present, with the expectation of improving the anti-HIV activity, safety, and druggability. Among the deuterated compounds, the exemplary compound <b>5a</b> (<b>ZK-316</b>) exhibited potent and broad-spectrum activity against wild-type and clinically observed mutant strains, with EC<sub>50</sub> values ranging from 0.99 to 75.1 nM, surpassing that of the hit compound <b>3</b> (EC<sub>50</sub> = 1.86–795.76 nM). Moreover, low cytotoxicity was exhibited by <b>ZK-316</b> (CC<sub>50</sub> > 225 nM), which was over 36.8 times lower than that of compound <b>3</b>, and high selectivity was also shown. Not only was there no apparent inhibition of cytochrome P450 (CYP) enzymes, but also low human ether-à-go-go-related gene (hERG) toxicity was found. And favorable pharmacokinetic profiles were shown as well, with a bioavailability of 29%, all of which indicated its promising druggability. Additionally, the identification of the metabolites of <b>ZK-316</b> was carried out to verify the stability of the deuterated methyl groups within human liver microsomes. These results offer valuable insights into the development of deuterated non-nucleoside reverse transcriptase inhibitors (NNRTIs) for human immunodeficiency virus (HIV) therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782975","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 : 2025-04-05DOI: 10.1021/acs.jmedchem.4c02941
Julien Hazemann, Thierry Kimmerlin, Aengus Mac Sweeney, Geoffroy Bourquin, Roland Lange, Daniel Ritz, Sylvia Richard-Bildstein, Sylvain Regeon, Paul Czodrowski
In this study, we performed the hit-to-lead optimization of a SARS-CoV-2 Mpro diazepane hit (identified by computational methods in a previous work) by combining computational simulations with high-throughput medicinal chemistry (HTMC). Leveraging the 3D structural information of Mpro, we refined the original hit by targeting the S1 and S2 binding pockets of the protein. Additionally, we identified a novel exit vector pointing toward the S1′ pocket, which significantly enhanced the binding affinity. This strategy enabled us to transform, rapidly with a limited number of compounds synthesized, a 14 μM hit into a potent 16 nM lead compound, for which key pharmacological properties were subsequently evaluated. This result demonstrated that combining computational technologies such as machine learning, molecular docking, and molecular dynamics simulation with HTMC can efficiently accelerate hit identification and subsequent lead generation.
{"title":"Accelerating the Hit-To-Lead Optimization of a SARS-CoV-2 Mpro Inhibitor Series by Combining High-Throughput Medicinal Chemistry and Computational Simulations","authors":"Julien Hazemann, Thierry Kimmerlin, Aengus Mac Sweeney, Geoffroy Bourquin, Roland Lange, Daniel Ritz, Sylvia Richard-Bildstein, Sylvain Regeon, Paul Czodrowski","doi":"10.1021/acs.jmedchem.4c02941","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02941","url":null,"abstract":"In this study, we performed the hit-to-lead optimization of a SARS-CoV-2 Mpro diazepane hit (identified by computational methods in a previous work) by combining computational simulations with high-throughput medicinal chemistry (HTMC). Leveraging the 3D structural information of Mpro, we refined the original hit by targeting the S1 and S2 binding pockets of the protein. Additionally, we identified a novel exit vector pointing toward the S1′ pocket, which significantly enhanced the binding affinity. This strategy enabled us to transform, rapidly with a limited number of compounds synthesized, a 14 μM hit into a potent 16 nM lead compound, for which key pharmacological properties were subsequently evaluated. This result demonstrated that combining computational technologies such as machine learning, molecular docking, and molecular dynamics simulation with HTMC can efficiently accelerate hit identification and subsequent lead generation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782828","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 : 2025-04-05DOI: 10.1021/acs.jmedchem.5c00403
Cheung-Hin Hung, Ka Hin Chan, Wai-Po Kong, Ruo-Lan Du, Kang Ding, Zhiguang Liang, Yong Wang, Kwok-Yin Wong
Photosensitizers (PSs) with aggregation-induced emission (AIE) properties have gained popularity for treating bacterial infections. However, most AIE PSs have a poor water solubility and low selectivity, limiting their applications in biological systems. Herein, we report a water-soluble and bacteria-targeting AIE PS that exhibits minimum cytotoxicity toward human cells with and without light irradiation. Acting as a narrow-spectrum antibacterial agent without light irradiation, TPA-1 eradicates planktonic Staphylococcus aureus and inhibits biofilm formation by targeting the S. aureus membrane, inhibiting the supercoiling activity of S. aureus DNA gyrase, and causing the downregulation of multiple essential proteins. Upon light irradiation, TPA-1 generates reactive oxygen species (ROS) that cause membrane damage, resulting in excellent antiplanktonic and antibiofilm activities against S. aureus and Pseudomonas aeruginosa, significantly reducing the number of viable bacteria in biofilms and promoting wound healing in vivo.
{"title":"A Water-Soluble Aggregation-Induced Emission Photosensitizer with Intrinsic Antibacterial Activity as an Antiplanktonic and Antibiofilm Therapeutic Agent","authors":"Cheung-Hin Hung, Ka Hin Chan, Wai-Po Kong, Ruo-Lan Du, Kang Ding, Zhiguang Liang, Yong Wang, Kwok-Yin Wong","doi":"10.1021/acs.jmedchem.5c00403","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00403","url":null,"abstract":"Photosensitizers (PSs) with aggregation-induced emission (AIE) properties have gained popularity for treating bacterial infections. However, most AIE PSs have a poor water solubility and low selectivity, limiting their applications in biological systems. Herein, we report a water-soluble and bacteria-targeting AIE PS that exhibits minimum cytotoxicity toward human cells with and without light irradiation. Acting as a narrow-spectrum antibacterial agent without light irradiation, TPA-1 eradicates planktonic <i>Staphylococcus aureus</i> and inhibits biofilm formation by targeting the <i>S. aureus</i> membrane, inhibiting the supercoiling activity of <i>S. aureus</i> DNA gyrase, and causing the downregulation of multiple essential proteins. Upon light irradiation, TPA-1 generates reactive oxygen species (ROS) that cause membrane damage, resulting in excellent antiplanktonic and antibiofilm activities against <i>S. aureus</i> and <i>Pseudomonas aeruginosa</i>, significantly reducing the number of viable bacteria in biofilms and promoting wound healing <i>in vivo</i>.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"217 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782829","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}
A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims of inducing DNA strand damage and inhibiting DNA repair. These complexes showed good antiproliferative activity against a range of cancer cell lines. Enhanced intracellular uptake of platinum and PROTAC was observed. Multiple mechanisms of action were identified, including the induction of DNA damage, disruption of DNA repair, and activation of mitochondrial-dependent apoptosis. One of the Pt(IV)-PROTACs, CW-2, showed excellent antitumor activity in a xenograft mouse model. These results suggest that Pt(IV)-PROTAC represents a promising strategy for the development of novel antitumor therapeutics.
我们设计并合成了一类铂（IV）-PROTAC 复合物，具有诱导 DNA 链损伤和抑制 DNA 修复的双重目的。这些复合物对一系列癌细胞株显示出良好的抗增殖活性。观察到铂和 PROTAC 在细胞内的吸收增强。研究发现了多种作用机制，包括诱导 DNA 损伤、破坏 DNA 修复和激活线粒体依赖性凋亡。其中一种铂(IV)-PROTAC--CW-2，在异种移植小鼠模型中显示出卓越的抗肿瘤活性。这些结果表明，Pt(IV)-PROTAC 是开发新型抗肿瘤疗法的一种有前途的策略。
{"title":"Pt(IV)-PROTAC Complexes with Synergistic Antitumor Activity and Enhanced Membrane Permeability","authors":"Cheng-xin Li, Zhi-ru Zou, Shan Xu, Jia-hui Shi, Yong Zou, Ming Yan, Xue-jing Zhang","doi":"10.1021/acs.jmedchem.4c02909","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02909","url":null,"abstract":"A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims of inducing DNA strand damage and inhibiting DNA repair. These complexes showed good antiproliferative activity against a range of cancer cell lines. Enhanced intracellular uptake of platinum and PROTAC was observed. Multiple mechanisms of action were identified, including the induction of DNA damage, disruption of DNA repair, and activation of mitochondrial-dependent apoptosis. One of the Pt(IV)-PROTACs, <b>CW-2</b>, showed excellent antitumor activity in a xenograft mouse model. These results suggest that Pt(IV)-PROTAC represents a promising strategy for the development of novel antitumor therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782977","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 : 2025-04-04DOI: 10.1021/acs.jmedchem.5c00005
Tingting Liang, Jie Tu, Qianqian He, Piaopiao Zou, Wanzhen Yang, Yahui Huang, Na Liu, Chunquan Sheng
The morbidity and mortality of invasive fungal infections are increasing rapidly. Developing effective and safe antifungal drugs with novel chemical scaffolds and mechanisms is urgently needed. On the basis of our previously identified Pdr1-KIX inhibitor 1, a series of new pyrazolone-carbothioamide derivatives were designed and assayed. In particular, compound A7 showed picomolar in vitro antifungal activity against Candida glabrata (MIC = 0.00012 μg/mL) and Cryptococcus neoformans (MIC = 0.00012 μg/mL), with excellent antivirulence effects. In the murine candidiasis and cryptococcosis models, compound A7 exhibited potent in vivo therapeutic efficacy. Interestingly, a mechanism investigation revealed that the antifungal activity of compound A7 is independent of KIX binding. It disrupted the iron homeostasis of fungal cells and then induced oxidative stress damages by accumulating the reactive oxygen species and lipid peroxides. Therefore, compound A7 represents a promising lead with a new mechanism of action to combat candidiasis and cryptococcosis.
{"title":"Discovery of New Pyrazolone Carbothioamide Derivatives as Potent Antifungal Agents for the Treatment of Candidiasis and Cryptococcosis","authors":"Tingting Liang, Jie Tu, Qianqian He, Piaopiao Zou, Wanzhen Yang, Yahui Huang, Na Liu, Chunquan Sheng","doi":"10.1021/acs.jmedchem.5c00005","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00005","url":null,"abstract":"The morbidity and mortality of invasive fungal infections are increasing rapidly. Developing effective and safe antifungal drugs with novel chemical scaffolds and mechanisms is urgently needed. On the basis of our previously identified Pdr1-KIX inhibitor <b>1</b>, a series of new pyrazolone-carbothioamide derivatives were designed and assayed. In particular, compound <b>A7</b> showed picomolar <i>in vitro</i> antifungal activity against <i>Candida glabrata</i> (MIC = 0.00012 μg/mL) and <i>Cryptococcus neoformans</i> (MIC = 0.00012 μg/mL), with excellent antivirulence effects. In the murine candidiasis and cryptococcosis models, compound <b>A7</b> exhibited potent <i>in vivo</i> therapeutic efficacy. Interestingly, a mechanism investigation revealed that the antifungal activity of compound <b>A7</b> is independent of KIX binding. It disrupted the iron homeostasis of fungal cells and then induced oxidative stress damages by accumulating the reactive oxygen species and lipid peroxides. Therefore, compound <b>A7</b> represents a promising lead with a new mechanism of action to combat candidiasis and cryptococcosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776195","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 : 2025-04-04DOI: 10.1021/acs.jmedchem.5c00402
Ruolin Cao, Maoying Zhang, Minggang Qi, Zhen Zhang, Christophe Morisseau, Chunwei Zhou, Tianqi Sun, Junning Zhuang, Lu Chen, Cheng Xu, Zhongbo Liu, Bruce D. Hammock, Guoliang Chen
The peroxisome proliferator-activated receptor-γ (PPARγ) serves as a pivotal regulator of lipid balance, adipogenesis, and inflammatory processes. PPARγ full agonists display strong curative effects but also serious adverse effects. Here, we found a novel 4-(cyclohexyloxy)phenyl acetate scaffold with partial PPARγ agonist activity, and its structure–activity relationship was studied. We also describe the structure-guided lead optimization of orally bioavailable SP-C01 as a dual modulator of soluble epoxide hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of SP-C01 at a dose of 5 g/kg resulted in excellent safety; a significant reduction in the negative consequences of lipid accumulation and water–sodium retention; and no gastrointestinal adverse effects, weight gain, or cardiotoxicity. In addition, SP-C01 has shown a better effect than pioglitazone (Pio.) in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, SP-C01 has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.
{"title":"Structure-Based Design and Optimization Lead to the Identification of a Novel Potent sEH Inhibitor with PPARγ Partial Agonist Activity against Inflammatory and Metabolic-Related Diseases","authors":"Ruolin Cao, Maoying Zhang, Minggang Qi, Zhen Zhang, Christophe Morisseau, Chunwei Zhou, Tianqi Sun, Junning Zhuang, Lu Chen, Cheng Xu, Zhongbo Liu, Bruce D. Hammock, Guoliang Chen","doi":"10.1021/acs.jmedchem.5c00402","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00402","url":null,"abstract":"The peroxisome proliferator-activated receptor-γ (PPARγ) serves as a pivotal regulator of lipid balance, adipogenesis, and inflammatory processes. PPARγ full agonists display strong curative effects but also serious adverse effects. Here, we found a novel 4-(cyclohexyloxy)phenyl acetate scaffold with partial PPARγ agonist activity, and its structure–activity relationship was studied. We also describe the structure-guided lead optimization of orally bioavailable <b>SP-C01</b> as a dual modulator of soluble epoxide hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of <b>SP-C01</b> at a dose of 5 g/kg resulted in excellent safety; a significant reduction in the negative consequences of lipid accumulation and water–sodium retention; and no gastrointestinal adverse effects, weight gain, or cardiotoxicity. In addition, <b>SP-C01</b> has shown a better effect than pioglitazone (<b>Pio.</b>) in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, <b>SP-C01</b> has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782830","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 : 2025-04-04DOI: 10.1021/acs.jmedchem.4c02335
Loukas Ieremias, Asmita Manandhar, Katrine Schultz-Knudsen, Mads Holmgaard Kaspersen, Christina Ioanna Vrettou, Elisabeth Rexen Ulven, Trond Ulven
GPR84 is an orphan GPCR that is expressed primarily in immune cells such as neutrophils and macrophages, and that modulates immune responses during inflammation. The receptor has appeared as a promising drug target, and accumulating evidence indicates that GPR84 inhibition is a viable approach for treatment of various inflammatory and fibrotic disorders. Herein, we report the discovery of a minor structural modification resulting in functional switch of agonists to inverse agonists. Subsequent SAR explorations led to the identification of low-nanomolar potency inverse agonists and antagonists, as exemplified by TUG-2181 (40g). Representative compounds exhibited good physicochemical properties, selectivity over other free fatty acid receptors, and the ability to fully inhibit GPR84-mediated neutrophil activation.
GPR84 是一种孤儿 GPCR，主要在中性粒细胞和巨噬细胞等免疫细胞中表达，并在炎症过程中调节免疫反应。该受体已成为一个有前景的药物靶点，越来越多的证据表明，抑制 GPR84 是治疗各种炎症和纤维化疾病的可行方法。在此，我们报告发现了一种微小的结构修饰，这种修饰导致了激动剂向反向激动剂的功能转换。随后的 SAR 探索发现了低纳摩尔效力的反向激动剂和拮抗剂，TUG-2181（40g）就是一个例子。代表性化合物具有良好的理化特性、对其他游离脂肪酸受体的选择性以及完全抑制 GPR84 介导的中性粒细胞活化的能力。
{"title":"Minimal Structural Variation of GPR84 Full Agonist Causes Functional Switch to Inverse Agonism.","authors":"Loukas Ieremias, Asmita Manandhar, Katrine Schultz-Knudsen, Mads Holmgaard Kaspersen, Christina Ioanna Vrettou, Elisabeth Rexen Ulven, Trond Ulven","doi":"10.1021/acs.jmedchem.4c02335","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02335","url":null,"abstract":"<p><p>GPR84 is an orphan GPCR that is expressed primarily in immune cells such as neutrophils and macrophages, and that modulates immune responses during inflammation. The receptor has appeared as a promising drug target, and accumulating evidence indicates that GPR84 inhibition is a viable approach for treatment of various inflammatory and fibrotic disorders. Herein, we report the discovery of a minor structural modification resulting in functional switch of agonists to inverse agonists. Subsequent SAR explorations led to the identification of low-nanomolar potency inverse agonists and antagonists, as exemplified by TUG-2181 (<b>40g</b>). Representative compounds exhibited good physicochemical properties, selectivity over other free fatty acid receptors, and the ability to fully inhibit GPR84-mediated neutrophil activation.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778606","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 : 2025-04-03DOI: 10.1021/acs.jmedchem.5c00419
Rozalia A. Dodean, Yuexin Li, Xiaowei Zhang, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Ravi Chetree, Karl Kudyba, Sharon McEnearney, Patricia J. Lee, Cameron Blount, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Kennedy Mdaki, Susan Leed, Monica L. Martin, Brandon S. Pybus, Sovitj Pou, Rolf W. Winter, Katherine M. Liebman, Rachel Williams, Amrendra Kumar, Anongruk Chim-Ong, Liwang Cui, Stephen Orena, Jackson Assimwe, Innocent Tibagambirwa, Oswald Byaruhanga, Patrick Angutoko, Jennifer Legac, Oriana Kreutzfeld, Philip J. Rosenthal, Roland A. Cooper, Aaron Nilsen, Michael K. Riscoe, Alison Roth, Papireddy Kancharla, Jane X. Kelly
Building from our previous lead compound T111 (1) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and Plasmodium berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using Plasmodium cynomolgi, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound 28 (T229) provided full LS protection and a sustained blood-stage cure for murine P. berghei infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound 28 demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.
我们以前的先导化合物 T111（1）对恶性疟原虫无性血液期（ABS）和伯格氏疟原虫肝脏期（LS）寄生虫都具有活性，在此基础上，我们系统地设计和合成了下一代抗疟吖啶酮。大量新生成的吖啶酮类化合物对 ABS 和 LS 寄生虫都显示出了极佳的抗疟活性，并且具有良好的安全性和代谢特性。在一项使用疟原虫进行的高通量低佐虫杀灭试验中，这些吖啶酮在预防性用药和根治性用药模式下都能显著抑制裂头蚴和低佐虫的形成。值得注意的是，新一代吖啶酮大大减轻了与阿托伐醌的交叉耐药性。具有代表性的化合物 28（T229）为小鼠伯格氏疟原虫感染提供了全面的 LS 保护，并以 10 毫克/千克/天和 40 毫克/千克/天的口服剂量实现了持续的血期治愈。此外，化合物 28 的遗传毒性和心脏毒性风险都很低，而且对抗病毒疗法耐药寄生虫非常有效。这项研究首次证明了新型吖啶酮家族具有强大的抗复发性寄生虫活性。
{"title":"Development of Next-Generation Antimalarial Acridones with Radical Cure Potential","authors":"Rozalia A. Dodean, Yuexin Li, Xiaowei Zhang, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Ravi Chetree, Karl Kudyba, Sharon McEnearney, Patricia J. Lee, Cameron Blount, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Kennedy Mdaki, Susan Leed, Monica L. Martin, Brandon S. Pybus, Sovitj Pou, Rolf W. Winter, Katherine M. Liebman, Rachel Williams, Amrendra Kumar, Anongruk Chim-Ong, Liwang Cui, Stephen Orena, Jackson Assimwe, Innocent Tibagambirwa, Oswald Byaruhanga, Patrick Angutoko, Jennifer Legac, Oriana Kreutzfeld, Philip J. Rosenthal, Roland A. Cooper, Aaron Nilsen, Michael K. Riscoe, Alison Roth, Papireddy Kancharla, Jane X. Kelly","doi":"10.1021/acs.jmedchem.5c00419","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00419","url":null,"abstract":"Building from our previous lead compound T111 (<b>1</b>) possessing activity against both <i>Plasmodium falciparum</i> asexual blood-stage (ABS) and <i>Plasmodium berghei</i> liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using <i>Plasmodium cynomolgi</i>, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound <b>28</b> (T229) provided full LS protection and a sustained blood-stage cure for murine <i>P. berghei</i> infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound <b>28</b> demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776197","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 : 2025-04-03DOI: 10.1021/acs.jmedchem.4c02860
Giovanni Ribaudo, Andrea Achille Taccani, Alessandra Gianoncelli
While naloxone remains the antidote for opioid overdoses, more efficient tools are required to effectively combat this growing crisis. Vaccines and antibodies targeting substances of abuse appear to be a novel and promising approach to tackling the fentanyl and opioid epidemic. After an initial in-depth rundown on the pharmacodynamics of the substances involved from a structural and mechanistic standpoint, and a brief overview of pharmacological approaches used in clinical settings for managing overdoses and opioid addiction, this Perspective will be mainly focused on these innovative strategies, based on the development of antibodies binding and sequestering substances of abuse and on their generation in vivo through vaccines. The most promising approaches will be examined, from production techniques to their potential clinical applications, analyzing the structures and mechanisms of antibody–substance interactions and comparing these with receptor binding processes.
{"title":"Fentanyl–Antibody Interaction as a Novel Strategy against Opiates and Opioids Abuse","authors":"Giovanni Ribaudo, Andrea Achille Taccani, Alessandra Gianoncelli","doi":"10.1021/acs.jmedchem.4c02860","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02860","url":null,"abstract":"While naloxone remains <i>the</i> antidote for opioid overdoses, more efficient tools are required to effectively combat this growing crisis. Vaccines and antibodies targeting substances of abuse appear to be a novel and promising approach to tackling the fentanyl and opioid epidemic. After an initial in-depth rundown on the pharmacodynamics of the substances involved from a structural and mechanistic standpoint, and a brief overview of pharmacological approaches used in clinical settings for managing overdoses and opioid addiction, this Perspective will be mainly focused on these innovative strategies, based on the development of antibodies binding and sequestering substances of abuse and on their generation <i>in vivo</i> through vaccines. The most promising approaches will be examined, from production techniques to their potential clinical applications, analyzing the structures and mechanisms of antibody–substance interactions and comparing these with receptor binding processes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"73 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766828","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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