Expert Opinion on Drug Discovery最新文献_第6页

The role of rodent behavioral models of schizophrenia in the ongoing search for novel antipsychotics. 精神分裂症啮齿动物行为模型在寻找新型抗精神病药物中的作用。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2025-01-28 DOI: 10.1080/17460441.2025.2459807

Hugo Cano-Ramírez, Kurt Leroy Hoffman

{"title":"The role of rodent behavioral models of schizophrenia in the ongoing search for novel antipsychotics.","authors":"Hugo Cano-Ramírez, Kurt Leroy Hoffman","doi":"10.1080/17460441.2025.2459807","DOIUrl":"10.1080/17460441.2025.2459807","url":null,"abstract":"Introduction: Existing pharmacotherapies for schizophrenia have not progressed beyond targeting dopamine and serotonin neurotransmission. Rodent models of schizophrenia are a necessary tool for elucidating neuropathological processes and testing potential pharmacotherapies, but positive preclinical results in rodent models often do not translate to positive results in the clinic.Areas covered: The authors reviewed PubMed for studies that applied rodent behavioral models of schizophrenia to assess the antipsychotic potential of several novel pharmacotherapies currently under investigation. These included acetylcholinesterase inhibitors, muscarinic and nicotinic acetylcholine (ACh) receptor agonists and positive allosteric modulators (PAMs), histamine H3 receptor antagonist/inverse, calcium channel modulators, trace amino acid receptor (TAAR) agonists, and phosphodiesterase 10A (PDE10A) inhibitors. The authors discuss the extent to which the results of preclinical studies of these drugs in rodent models have predicted clinical efficacy.Expert opinion: Although published preclinical studies of these drugs were largely positive, clinical results were often modest or negative. This lack of correspondence is likely due to many factors, including differences in experimental design, poor translation of effective dosing from preclinical to clinical studies, and large inter-individual variation of the human population as compared to laboratory rodents. Closing the gap between preclinical and clinical studies will require strategies aimed at reducing the impact of these factors.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"217-231"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The importance of preclinical models for cholangiocarcinoma drug discovery. 临床前模型对胆管癌药物发现的重要性。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2025-02-05 DOI: 10.1080/17460441.2025.2457637

Felix J Krendl, Florian Primavesi, Rupert Oberhuber, Daniel Neureiter, Matthias Ocker, Dino Bekric, Tobias Kiesslich, Christian Mayr

{"title":"The importance of preclinical models for cholangiocarcinoma drug discovery.","authors":"Felix J Krendl, Florian Primavesi, Rupert Oberhuber, Daniel Neureiter, Matthias Ocker, Dino Bekric, Tobias Kiesslich, Christian Mayr","doi":"10.1080/17460441.2025.2457637","DOIUrl":"10.1080/17460441.2025.2457637","url":null,"abstract":"Introduction: Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.Areas covered: The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens. All these models have individual advantages, disadvantages and limitations that need to be considered depending on the desired application.Expert opinion: In addition to potential cost limitations, availability of BTC cell types, time required for model establishment and growth success rate, the individual models differently reflect relevant characteristics such as tumor heterogeneity, spatial tumor-stroma microenvironment interactions, metabolic and nutritional gradients and immunological interactions. Therefore, a consequent combination of different models may be required to improve clinical study outcomes by strengthening the preclinical data basis.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"205-216"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel anticancer drug discovery efforts targeting glycosylation: the emergence of fluorinated monosaccharides analogs. 针对糖基化的新型抗癌药物的发现：氟化单糖类似物的出现。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2025-01-06 DOI: 10.1080/17460441.2024.2444375

Ana F Costa, Andreia Teixeira, Celso A Reis, Catarina Gomes

{"title":"Novel anticancer drug discovery efforts targeting glycosylation: the emergence of fluorinated monosaccharides analogs.","authors":"Ana F Costa, Andreia Teixeira, Celso A Reis, Catarina Gomes","doi":"10.1080/17460441.2024.2444375","DOIUrl":"10.1080/17460441.2024.2444375","url":null,"abstract":"Introduction: Glycosylation is an essential enzymatic process of building glycan structures that occur mainly within the cell and gives rise to a diversity of cell surface and secreted glycoconjugates. These glycoconjugates play vital roles, for instance in cellcell adhesion, interaction and communication, activation of cell surface receptors, inflammatory response and immune recognition. This controlled and wellcoordinated enzymatic process is altered in cancer, leading to the biosynthesis of cancerassociated glycans, which impact glycandependent biological roles.Areas covered: In this review, the authors discuss the importance of targeting cancerassociated glycans through potent glycan biosynthesis inhibitors. It focuses on the use of analogs, providing an overview of findings involving these in cancer. The highly explored fluorinated monosaccharide analogs targeting aberrant glycosylation are described, aiming to inspire advances in the field.Expert opinion: Altered glycosylation, such as increased sialylation and fucosylation, is a feature in cancer and has been shown to play key roles in several malignant properties of cancer cells. Strategies aiming at remodeling cancer cells´ glycome are emerging and present a huge potential for cancer therapy. Fluorinated monosaccharides have been gathering promising preclinical results as novel cancer drugs. Nevertheless, cancer specific targeting strategies must be considered to avoid significant sideeffects.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"193-203"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Lessons learned from phenotypic drug discovery efforts. 从表型药物发现工作中汲取的经验教训。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2024-12-18 DOI: 10.1080/17460441.2024.2442741

David C Swinney

引用次数: 0

Human pluripotent stem cell (hPSC)-derived models for autism spectrum disorder drug discovery. 人类多能干细胞（hPSC）衍生模型用于自闭症谱系障碍药物发现。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2024-12-24 DOI: 10.1080/17460441.2024.2416484

Lingdi Nie, Courtney Irwin, Sarah Geahchan, Karun K Singh

{"title":"Human pluripotent stem cell (hPSC)-derived models for autism spectrum disorder drug discovery.","authors":"Lingdi Nie, Courtney Irwin, Sarah Geahchan, Karun K Singh","doi":"10.1080/17460441.2024.2416484","DOIUrl":"10.1080/17460441.2024.2416484","url":null,"abstract":"Introduction: Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental disorder (NDD) with genetic and environmental origins. Currently, there are no effective pharmacological treatments targeting core ASD features. This leads to unmet medical needs of individuals with ASD and requires relevant human disease models recapitulating genetic and clinical heterogeneity to better understand underlying mechanisms and identify potential pharmacological therapies. Recent advancements in stem cell technology have enabled the generation of human pluripotent stem cell (hPSC)-derived two-dimensional (2D) and three-dimensional (3D) neural models, which serve as powerful tools for ASD modeling and drug discovery.Areas covered: This article reviews the applications of hPSC-derived 2D and 3D neural models in studying various forms of ASD using pharmacological perturbation and drug screenings, highlighting the potential use of these models to develop novel pharmacological treatment strategies for ASD.Expert opinion: hPSC-derived models recapitulate early human brain development spatiotemporally and have allowed patient-specific mechanistic investigation and therapeutic development using advanced molecular technologies, which will contribute to precision medicine for ASD therapy. Improvements are still required in hPSC-based models to further enhance their physiological relevance, clinical translation, and scalability for ASD drug discovery.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"233-251"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Animal models of Kabuki syndrome and their applicability to novel drug discovery. 歌舞伎综合征的动物模型及其在新药开发中的适用性。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-01 Epub Date: 2025-02-03 DOI: 10.1080/17460441.2025.2457624

Mareike Mertens, Leen Khalife, Xiaoting Ma, Olaf Bodamer

{"title":"Animal models of Kabuki syndrome and their applicability to novel drug discovery.","authors":"Mareike Mertens, Leen Khalife, Xiaoting Ma, Olaf Bodamer","doi":"10.1080/17460441.2025.2457624","DOIUrl":"10.1080/17460441.2025.2457624","url":null,"abstract":"Introduction: Kabuki Syndrome (KS) is a rare genetic disorder characterized by distinctive facial features, intellectual disability, and multiple congenital anomalies. It is caused by pathogenic variants in the KMT2D and KDM6A genes. Despite its significant disease burden, there are currently no approved therapies for KS, highlighting the need for advanced research and therapeutic development.Areas covered: This review examines the use of animal models in KS research, including mice, fish, frogs, and nematodes. These models replicate key mechanistic and clinical aspects of Kabuki Syndrome, facilitating preclinical studies to demonstrate therapeutic efficacy. The literature search focused on identifying studies that utilized these models to investigate the pathophysiology of Kabuki Syndrome and evaluate potential treatments.Expert opinion: Refining animal models is essential to enhance their relevance to human disease and accelerate the development of effective therapies for Kabuki Syndrome. Insights from these models are invaluable in understanding underlying molecular mechanisms and identifying therapeutic targets. Continued research and collaboration are crucial to translating these findings into clinical practice, offering hope for future treatments.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"253-265"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Approach advancements for engineering novel peptide analogs of existing lantibiotics: where are we today? 现有抗生素的工程新型肽类似物的进展：我们今天在哪里？

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-21 DOI: 10.1080/17460441.2024.2441351

Thushinari Joseph, Leif Smith

{"title":"Approach advancements for engineering novel peptide analogs of existing lantibiotics: where are we today?","authors":"Thushinari Joseph, Leif Smith","doi":"10.1080/17460441.2024.2441351","DOIUrl":"10.1080/17460441.2024.2441351","url":null,"abstract":"Introduction: The emergence of antibiotic resistance among the clinically important bacterial pathogens has increased healthcare costs and reduced patient safety and quality of life. Lantibiotics is a large class of ribosomally synthesized, and posttranslationally modified peptides have been the primary focus of numerous research aimed at discovering compounds for treating bacterial infections.Areas covered: The article explains the most up to date hierarchy of methods followed in the field for high throughput screening of lantibiotics/analogs with improved therapeutic properties. Herein, we explain how the structure and the biosynthesis of lantibiotics can be manipulated for the expansion of the horizon of lantibiotic potency. Furthermore, we discuss the lantibiotic analogs that have demonstrated the efficacy against bacterial pathogens of interest in animal models.Expert opinion: In this current age of rapidly advancing antimicrobial resistance, there is a dire need for the development of therapeutic agents that possess distinct mechanisms of action to existing modes of treatment. Recent advances in the understanding of many of the lantibiotic biosynthesis systems and the discovery of new analogs with superior properties to the native compound may have paved the way for the development of a much-needed novel potent class of antibiotic.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"17-30"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Evolution of antisense oligonucleotides: navigating nucleic acid chemistry and delivery challenges. 反义寡核苷酸的演变：驾驭核酸化学和递送挑战。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1080/17460441.2024.2440095

Ruchi Ruchi, Govind Mukesh Raman, Vikas Kumar, Raman Bahal

{"title":"Evolution of antisense oligonucleotides: navigating nucleic acid chemistry and delivery challenges.","authors":"Ruchi Ruchi, Govind Mukesh Raman, Vikas Kumar, Raman Bahal","doi":"10.1080/17460441.2024.2440095","DOIUrl":"10.1080/17460441.2024.2440095","url":null,"abstract":"Introduction: Antisense oligonucleotide (ASO) was established as a viable therapeutic option for genetic disorders. ASOs can target RNAs implicated in various diseases, including upregulated mRNA and pre-mRNA undergoing abnormal alternative splicing events. Therapeutic applications of ASOs have been proven with the Food and Drug Administration approval of several drugs in recent years. Earlier enzymatic stability and delivery remains a big challenge for ASOs. Introducing new chemical modifications and new formulations resolving the issues related to the nuclease stability and delivery of the ASOs. Excitingly, ASOs-based bioconjugates that target the hepatocyte have gained much attraction. Efforts are ongoing to increase the therapeutic application of the ASOs to the extrahepatic tissue as well.Area covered: We have briefly discussed the mechanism of ASOs, the development of new chemistries, and delivery strategies for ASO-based drug discovery and development. The discussion focuses more on the already approved ASOs and those in the clinical development stage.Expert opinion: To expand the clinical application of ASOs, continuous effort is required to develop precise delivery strategies for targeting extrahepatic tissue to minimize the off-target effects.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"63-80"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in the design and development of chemical modulators of the voltage-gated potassium channels K_V7.4 and K_V7.5. 电压门控钾通道KV.4和KV.5化学调节剂的设计与研制进展。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-09 DOI: 10.1080/17460441.2024.2438226

Jana Lemke, Maik Gollasch, Dmitry Tsvetkov, Lukas Schulig

{"title":"Advances in the design and development of chemical modulators of the voltage-gated potassium channels KV7.4 and KV7.5.","authors":"Jana Lemke, Maik Gollasch, Dmitry Tsvetkov, Lukas Schulig","doi":"10.1080/17460441.2024.2438226","DOIUrl":"10.1080/17460441.2024.2438226","url":null,"abstract":"Introduction: Hypertension remains a major public health concern, with significant morbidity and mortality worldwide. Despite the availability of various antihypertensive medications, blood pressure control remains suboptimal in many individuals. During the last decades, KV7.4 and KV7.5, which were already known from the view of neuronal regulation, emerged as possible important players in the regulation of vascular tone and blood pressure.Areas covered: This review covers physiological functions and current advancements in the development of KV7.4 and KV7.5 channel modulators. The authors highlight the structural elements likely to be important for the future design of KV7 subtype-selective modulators, underscoring their potential as an innovative hypertension treatment.Expert opinion: Extensive research has been focused on targeting neuronal KV7.2 and KV7.3 channels, while KV7.4 and KV7.5 attracted less attention. Many of the developed compounds represent derivatives of flupirtine or retigabine, whereby subtype channel selectivity has only been demonstrated for a handful of individual compounds. Novel substances address additional sites within the binding pocket by incorporating new functional groups. A comprehensive and systematic evaluation of a compound set with significant subtype selectivity should be performed. The discovery of new highly active, less toxic, and selective compounds, therefore, remains the goal of further research in the coming years.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"47-62"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 cautionary tale of paradox and false positives in cannabidiol research. 一个关于大麻二酚研究中悖论和假阳性的警世故事。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-01 Epub Date: 2024-12-17 DOI: 10.1080/17460441.2024.2441359

Peter S Cogan

{"title":"A cautionary tale of paradox and false positives in cannabidiol research.","authors":"Peter S Cogan","doi":"10.1080/17460441.2024.2441359","DOIUrl":"10.1080/17460441.2024.2441359","url":null,"abstract":"Introduction: Decades of research on cannabidiol (CBD) have identified thousands of purported cellular effects, and many of these have been proposed to correlate with a vast therapeutic potential. Yet despite the large volume of findings fueling broad optimism in this regard, few have translated into any demonstrable clinical benefit or even notable side effects. Therein resides the great paradox of CBD: a drug that appears to affect almost everything in vitro does not clearly do much of anything in a clinical setting.Areas covered: Comparative critical evaluation of literature searched in PubMed and Google Scholar discovers multiple instances of inconsistent and contradictory findings regarding the pharmacology and clinical effects of CBD, as well as several uncelebrated reports that suggest potential explanations for these observations. Many of those effects attributed to the ostensible pharmacologic activity of cannabidiol are almost certainly the product of false-positive experimental results and artifactual findings that are unlikely to be realized under physiologic conditions.Expert opinion: Concerns regarding the physiological relevance and translational potential of in vitro findings across the field of cannabinoid research are both far-reaching and demanding of attention in the form of appropriate experimental controls that remain almost universally absent.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"5-15"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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