RESUMO
Boron neutron capture therapy (BNCT) is expected to be a promising next-generation cancer treatment. In 2020, Japan, which has led the research on this treatment modality, was the first country in the world to approve BNCT. The boron agents that have been clinically applied in BNCT include a caged boron compound (mercaptoundecahydrododecaborate: BSH) and a boron-containing amino acid (p-boronophenylalanine: BPA). In particular, the BPA preparation Steboronine® is the only approved drug for BNCT. However, the problem with BPA is that it is poorly retained in the tumor and has very low solubility in water. This cannot be overlooked for BNCT, which requires large amounts of boron in the tumor. The high dosage volume, together with low tumor retention, leads to reduced therapeutic efficacy and increased physical burden on the patient. In the case of BSH, its insufficient penetration into the tumor is problematic. Based on drug delivery system (DDS) technology, we have developed a next-generation boron pharmaceutical superior to Steboronine®. Our approach involves the redevelopment of BPA using innovative ionic liquid formulation technology. Here, we describe previous boron agents and introduce our recent efforts in the development of boron compounds.
Assuntos
Boroidretos , Compostos de Boro , Terapia por Captura de Nêutron de Boro , Sistemas de Liberação de Medicamentos , Neoplasias , Fenilalanina , Terapia por Captura de Nêutron de Boro/métodos , Humanos , Neoplasias/radioterapia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Compostos de Boro/administração & dosagem , Fenilalanina/análogos & derivados , Compostos de Sulfidrila , Desenvolvimento de MedicamentosRESUMO
The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs. The pursuit of new therapeutic agents has been enhanced by the creation of specialized labeled chemical probes, which aid in target localization, mechanistic studies, assay development, and the establishment of biomarkers for target engagement. By fusing medicinal chemistry with chemical biology in a comprehensive, translational end-to-end drug discovery strategy, we have expedited the development of novel therapeutics. Additionally, this strategy promises to foster highly productive partnerships between industry and academia, as will be illustrated through various examples.
Assuntos
Química Farmacêutica , Descoberta de Drogas , Endocanabinoides , Endocanabinoides/metabolismo , Endocanabinoides/química , Humanos , Indústria Farmacêutica , Monoacilglicerol Lipases/metabolismo , Monoacilglicerol Lipases/antagonistas & inibidores , Desenvolvimento de Medicamentos , AcademiaRESUMO
Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.
Assuntos
Pericardite , Proteínas Recombinantes de Fusão , Recidiva , Humanos , Pericardite/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/administração & dosagem , Desenho de Fármacos , Desenvolvimento de Medicamentos , Interleucina-1/antagonistas & inibidores , Interleucina-1/metabolismoRESUMO
Many factors determine whether and when a class of therapeutic agents will be successfully developed and brought to market, and historians of science, entrepreneurs, drug developers, and clinicians should be interested in accounts of both successes and failures. Successes induce many participants and observers to document them, whereas failed efforts are often lost to history, in part because involved parties are typically unmotivated to document their failures. The GLP-1 class of drugs for diabetes and obesity have emerged over the past decade as clinical and financial blockbusters, perhaps soon becoming the highest single source of revenue for the pharmaceutical industry (Berk 2023). In that context, it is instructive to tell the story of the first commercial effort to develop this class of drugs for metabolic disease, and how, despite remarkable early success, the work was abandoned in 1990. Told by a key participant in the effort, this story documents history that would otherwise be lost and suggests a number of lessons about drug development that remain relevant today.
Assuntos
Desenvolvimento de Medicamentos , Peptídeo 1 Semelhante ao Glucagon , Humanos , Peptídeo 1 Semelhante ao Glucagon/história , Desenvolvimento de Medicamentos/história , História do Século XX , Hipoglicemiantes/história , Hipoglicemiantes/uso terapêutico , Indústria Farmacêutica/história , Obesidade/história , Obesidade/tratamento farmacológicoRESUMO
Over the last decade, a new paradigm for cancer therapies has emerged which leverages the immune system to act against the tumor. The novel mechanism of action of these immunotherapies has also introduced new challenges to drug development. Biomarkers play a key role in several areas of early clinical development of immunotherapies including the demonstration of mechanism of action, dose finding and dose optimization, mitigation and prevention of adverse reactions, and patient enrichment and indication prioritization. We discuss statistical principles and methods for establishing the prognostic, predictive aspect of a (set of) biomarker and for linking the change in biomarkers to clinical efficacy in the context of early development studies. The methods discussed are meant to avoid bias and produce robust and reproducible conclusions. This review is targeted to drug developers and data scientists interested in the strategic usage and analysis of biomarkers in the context of immunotherapies.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Desenvolvimento de Medicamentos , AnimaisRESUMO
Neglected tropical diseases (NTDs) pose a major threat in tropical zones for impoverished populations. Difficulty of access, adverse effects or low efficacy limit the use of current therapeutic options. Therefore, development of new drugs against NTDs is a necessity. Compounds containing an aminopyridine (AP) moiety are of great interest for the design of new anti-NTD drugs due to their intrinsic properties compared with their closest chemical structures. Currently, over 40 compounds with an AP moiety are on the market, but none is used against NTDs despite active research on APs. The aim of this review is to present the medicinal chemistry work carried out with these scaffolds, against protozoan NTDs: Trypanosoma cruzi, Trypanosoma brucei or Leishmania spp.
[Box: see text].
Assuntos
Aminopiridinas , Antiprotozoários , Doenças Negligenciadas , Trypanosoma brucei brucei , Trypanosoma cruzi , Doenças Negligenciadas/tratamento farmacológico , Humanos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Aminopiridinas/química , Aminopiridinas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Desenvolvimento de Medicamentos , Testes de Sensibilidade Parasitária , AnimaisRESUMO
Stress testing (also known as forced degradation) of pharmaceutical drug substances and products is a critical part of the drug development process, providing insight into the degradation pathways of drug substances and drug products. This information is used to support the development of stability-indicating methods (SIMs) capable of detecting pharmaceutically relevant degradation products that might potentially be observed during manufacturing, long-term storage, distribution, and use. Assessing mass balance of stressed samples is a key aspect of developing SIMs and is a regulatory expectation. However, the approaches to measure, calculate, and interpret mass balance can vary among different pharmaceutical companies. Such disparities also pose difficulties for health authorities when reviewing mass balance assessments, which may result in the potential delay of drug application approvals. The authors have gathered input from 10 pharma companies to map out a practical review of science-based approaches and technical details to assess and interpret mass balance results. Key concepts of mass balance are introduced, various mass balance calculations are demonstrated, and recommendations on how to investigate poor mass balance results are presented using real-world case studies. Herein we provide a single source reference on the topic of mass balance in pharmaceutical forced degradation for small molecule drug substances and drug products in support of regulatory submissions with the goal of facilitating a shared understanding among pharmaceutical scientists and health authorities.
Assuntos
Estabilidade de Medicamentos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Indústria Farmacêutica/métodos , Humanos , Desenvolvimento de Medicamentos/métodosRESUMO
Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ligação Proteica , Desenvolvimento de Medicamentos , Relação Estrutura-AtividadeRESUMO
Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.
Assuntos
Antineoplásicos , Dose Máxima Tolerável , Neoplasias , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Desenvolvimento de Medicamentos , Relação Dose-Resposta a DrogaRESUMO
INTRODUCTION: Recently, different actors have intensified their efforts to make drug development more participatory. They have produced many frameworks, tools and dedicated fora, where patients are portrayed as relevant stakeholders to be involved throughout the entire drug development trajectory. To better understand what such participatory efforts entail, in this article, we investigate how patient representation is configured in drug development and what patients can engage as representatives in this field. METHODS: This is a qualitative study based on the thematic analysis of 40 semistructured interviews with different stakeholders in the field and three patient engagement How-To guides (HTGs) complemented by observations of two sessions of the Patient Engagement Open Forum (PEOF) and a patient expert training of the European Patients' Academy on Therapeutic Innovation (EUPATI). FINDINGS: The emerging practices of patient engagement in drug development configure representation as hinging upon three types of knowledge-drug development knowledge, autobiographical knowledge and community knowledge-and a specific set of skills. We discern a new kind of representation based on these findings, termed 'knowledge-based representation', which appears to more accurately describe how patients are expected to represent others in drug development. CONCLUSION: Even though knowledge-based representation may be understood as an attempt to downplay the political aspects of representation in favour of its epistemic elements, the political processes involved in patient representation in drug development cannot be ignored. The extent to which reliance on knowledge-based representation will contribute to democratic decision-making is likely to depend on the resources needed to develop the types of knowledge relevant to representation work and on how these types of knowledge are determined. PATIENT OR PUBLIC CONTRIBUTION: Patient representatives and practitioners in the field of patient engagement (including 13 interviewees, representatives of EUPATI and HTG developers) gave feedback on the interpretation of the findings during a multistakeholder workshop we organised. We also sent an interviewee an extended draft and discussed it during an online meeting. Claudia Egher presented these findings at a PEOF session in June 2023, which further contributed to their validation.
Assuntos
Desenvolvimento de Medicamentos , Entrevistas como Assunto , Participação do Paciente , Pesquisa Qualitativa , Humanos , Participação dos InteressadosRESUMO
Aberrant or dysfunctional cellular enzymes are responsible for a wide range of diseases including cancer, neurodegenerative conditions, and metabolic disorders. Deficiencies in enzyme level or biofunction may lead to intracellular accumulation of substrate to toxic levels and interfere with overall cellular function, ultimately leading to cell damage, disease, and death. Marketed therapeutic interventions for inherited monogenic enzyme deficiency disorders include enzyme replacement therapy and small molecule chaperones. Novel approaches of in vivo gene therapy and ex vivo cell therapy are under clinical evaluation and provide promising opportunities to expand the number of available disease-modifying treatments. To support the development of these different therapeutics, assays to quantify the functional activity of protein enzymes have gained importance in the diagnosis of disease, assessment of pharmacokinetics and pharmacodynamic response, and evaluation of drug efficacy. In this review, we discuss the technical aspects of enzyme activity assays in the bioanalytical context, including assay design and format as well as the unique challenges and considerations associated with assay development, validation, and life cycle management.
Assuntos
Biomarcadores , Desenvolvimento de Medicamentos , Erros Inatos do Metabolismo , Humanos , Biomarcadores/metabolismo , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Desenvolvimento de Medicamentos/métodos , Ensaios Enzimáticos/métodos , Animais , Terapia de Reposição de Enzimas/métodosRESUMO
INTRODUCTION: Asthma is a common disease with a global burden of 358 million patients. Despite improvements in pharmacological and non-pharmacological treatments, many patients still do not achieve complete asthma control. Therefore, innovative pharmacotherapy is important. AREAS COVERED: Following a semi-structured search in Pubmed, an overview of advances in inhaled asthma therapy is provided, looking at innovations in digital inhalers, eco-friendly inhalers and novel inhaled biologic therapies, antibiotics and vaccines, as well as other potential novel asthma therapy targets. EXPERT OPINION: Digital inhalers, sending reminders and monitoring inhalation technique electronically, can support medication adherence and improve asthma control. To reduce the global warming potential of traditional aerosols used in pressurized metered-dose inhalers (HFA-134a, HFA-227ea), greener alternatives are under development (HFA-152a, HFO-1234ze) that are expected to be available by 2025. Current pharmacological advances in asthma therapy are mainly achieved by novel biologicals (anti-IgE, anti-IL5, anti-IL4/13, and anti-TSLP) targeting specific severe asthma phenotypes. While injection is the usual administration route for biologics and vaccines used in asthma, inhalation is an option being explored, although several (mainly formulation) challenges need to be overcome. Other potential novel future inhaled asthma therapies include anti-IL-33/ST2 biologicals and JAK inhibitors, all still requiring more clinical evidence.
Assuntos
Antiasmáticos , Asma , Humanos , Asma/tratamento farmacológico , Administração por Inalação , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Nebulizadores e Vaporizadores , Adesão à Medicação , Desenvolvimento de Medicamentos , AerossóisRESUMO
Misuse and accidental overdoses attributed to stimulants are escalating rapidly. These stimulants include methamphetamine, cocaine, amphetamine, ecstasy-type drugs, and prescription stimulants such as methylphenidate. Unlike opioids and alcohol, there are no therapies approved by the US Food and Drug Administration (FDA) to treat stimulant-use disorder. The high rate of relapse among this population highlights the insufficiency of current treatment options, which are limited to abstinence support programs and behavioral modification therapies. Here, we briefly outline recent regulatory actions taken by FDA to help support the development of new stimulant use disorder treatments and highlight several new therapeutics in the clinical development pipeline.
Assuntos
Estimulantes do Sistema Nervoso Central , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtornos Relacionados ao Uso de Substâncias/terapia , Animais , Desenvolvimento de Medicamentos , Estados UnidosRESUMO
Currently, artificial intelligence (AI), machine learning (ML), and deep learning (DL) are gaining increased interest in many fields, particularly in pharmaceutical research and development, where they assist in decision-making in complex situations. Numerous research studies and advancements have demonstrated how these computational technologies are used in various pharmaceutical research and development aspects, including drug discovery, personalized medicine, drug formulation, optimization, predictions, drug interactions, pharmacokinetics/ pharmacodynamics, quality control/quality assurance, and manufacturing processes. Using advanced modeling techniques, these computational technologies can enhance efficiency and accuracy, handle complex data, and facilitate novel discoveries within minutes. Furthermore, these technologies offer several advantages over conventional statistics. They allow for pattern recognition from complex datasets, and the models, typically developed from data-driven algorithms, can predict a given outcome (model output) from a set of features (model inputs). Additionally, this review discusses emerging trends and provides perspectives on the application of AI with quality by design (QbD) and the future role of AI in this field. Ethical and regulatory considerations associated with integrating AI into pharmaceutical technology were also examined. This review aims to offer insights to researchers, professionals, and others on the current state of AI applications in pharmaceutical research and development and their potential role in the future of research and the era of pharmaceutical Industry 4.0 and 5.0.
Assuntos
Inteligência Artificial , Desenvolvimento de Medicamentos , Pesquisa Farmacêutica , Pesquisa Farmacêutica/métodos , Desenvolvimento de Medicamentos/métodos , Humanos , Tecnologia Farmacêutica/métodos , Descoberta de Drogas/métodos , Aprendizado de Máquina , Controle de Qualidade , Medicina de Precisão/métodosRESUMO
With the COVID-19 pandemic, the importance of vaccines has been widely recognized and has led to increased research and development efforts. Vaccines also play a crucial role in cancer treatment by activating the immune system to target and destroy cancer cells. However, enhancing the efficacy of cancer vaccines remains a challenge. Adjuvants, which enhance the immune response to antigens and improve vaccine effectiveness, have faced limitations in recent years, resulting in few novel adjuvants being identified. The advancement of artificial intelligence (AI) technology in drug development has provided a foundation for adjuvant screening and application, leading to a diversification of adjuvants. This article reviews the significant role of tumor vaccines in basic research and clinical treatment and explores the use of AI technology to screen novel adjuvants from databases. The findings of this review offer valuable insights for the development of new adjuvants for next-generation vaccines.
Assuntos
Adjuvantes Imunológicos , Inteligência Artificial , COVID-19 , Vacinas Anticâncer , Neoplasias , Humanos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , COVID-19/prevenção & controle , COVID-19/imunologia , SARS-CoV-2/imunologia , Animais , Desenvolvimento de Vacinas , Desenvolvimento de MedicamentosRESUMO
INTRODUCTION: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting about 0.6% to 1.3% of the population, and is characterized primarily by mucocutaneous bleeding secondary to defective platelet adhesion and aggregation. Current therapeutic options for those with severe disease are limited and require frequent intravenous infusions. AREAS COVERED: This review discusses the current and recently completed clinical trials involving pathways to FVIII augmentation for the treatment of VWD. Clinical trials registered on clinicaltrials.gov and published data via PubMed searches through June 2024 were included. EXPERT OPINION: Available treatment options to those with VWD are limited in part due to limited clinical trials, the complexity of VWD types, and the pharmacokinetics of current treatment options. The development of therapeutic options that reduce treatment burden is necessary to improve quality of life and reduce bleeding complications and in recent years there has been an increased interest from industry to apply novel therapeutics for VWD. The FVIII mimetic, emicizumab, has demonstrated early success in patients with severe VWD and is a promising treatment option for those who require prophylaxis. Furthermore, products like efanesoctocog alfa (Altuviiio®) and BT200 have achieved enhanced VWF/FVIII half-life extension could expand the current treatment landscape while concurrently minimizing treatment burden.
Assuntos
Fator VIII , Doenças de von Willebrand , Animais , Humanos , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Desenvolvimento de Medicamentos , Fator VIII/uso terapêutico , Fator VIII/farmacocinética , Hemorragia , Qualidade de Vida , Índice de Gravidade de Doença , Doenças de von Willebrand/tratamento farmacológicoRESUMO
Alzheimer's disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.
Assuntos
Doença de Alzheimer , Desenvolvimento de Medicamentos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Ensaios Clínicos como Assunto , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteínas tau/metabolismo , Proteínas tau/genética , Proteínas tau/antagonistas & inibidoresRESUMO
Decades of evidence positioned IL-1ß as a master regulatory cytokine in acute and chronic inflammatory diseases. Approved biologics aimed at inhibiting IL-1 signaling have shown efficacy but variable safety. More recently, targeting NLRP3 activation, an upstream mediator of IL-1ß, has garnered the most attention. Aberrant NLRP3 activation has been demonstrated to participate in the progression of several pathological conditions from neurogenerative diseases to cardio-metabolic syndromes and cancer. Pharmacological and genetic strategies aimed to limit NLRP3 function have proven effective in many preclinical models of diseases. These evidences have lead to a significant effort in the generation and clinical testing of small orally active molecules that can target NLRP3. In this report, we discuss different properties of these molecules with translational potential and describe the technologies currently available to screen NLRP3 targeting molecules highlighting advantages and limitations of each method.
Assuntos
Desenvolvimento de Medicamentos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Interleucina-1beta/metabolismo , Interleucina-1beta/antagonistas & inibidores , Inflamassomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inflamação/tratamento farmacológicoRESUMO
The COVID-19 pandemic has highlighted the importance of efficient drug discovery in respiratory disease. The traditional set up of clinical trials is expensive and allows for significant attrition of new drugs, many of which undergo extensive safety testing before being abandoned for lack of efficacy. Phase 0 trials, named as they sit between pre-clinical research and phase I, allow for the testing of sub-clinical microdoses in humans to gather early pharmacokinetic (PK), pharmacodynamic (PD) and mechanistic data, before deciding on which drugs to advance further. This early data can improve the efficiency and cost effectiveness of drug development and reduce the extent of animal testing. Phase 0 trials traditionally have utilised sub-therapeutic microdoses of compounds administered intravenously with readouts focusing on PK - measured using highly sensitive methods such as accelerator mass spectrometry (AMS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) of peripheral blood, as well as whole-body positron emission tomography (PET). Mathematical models allow for extrapolation of this PK data to support the further testing of larger, systemically effective doses. However, this extrapolation method is limited at providing robust PD or target engagement/ mode of action data. Using an Intra-Target Microdosing (ITM) approach, a small compartment of the body (about 1% or less) is exposed to potentially clinically active local concentrations. This allows for the collection of PD data, evidence of target cell engagement, as well as the opportunity to extrapolate systemic PK and PD data. This approach has the potential within the pulmonary system for the study and rapid and cost-effective development of new and repurposed drugs.