Development of small molecule Protease-activated-receptor-2 antagonists as oral asthma therapeutics

开发小分子蛋白酶激活受体 2 拮抗剂作为口服哮喘治疗药物

基本信息

批准号：
10766584
负责人：
Scott Boitano
金额：
$ 30万
依托单位：
PARMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10766584
关键词：
ARRB2 Acute Adrenal Cortex Hormones Adrenergic beta-Agonists Adult Affect Allergens Alternaria Animal Model Animals Antibodies Antibody Therapy Area Arizona Asthma Biological Availability Biological Products Blocking Antibodies Bronchoconstriction Bronchodilation Businesses C57BL/6 Mouse Canis familiaris Cells Chronic Clinical Collaborations Complement Development Dictyoptera Dinoprostone Disease Drug Design Drug Kinetics Eosinophilia Epithelial Cells Epithelium Event Extrinsic asthma Feasibility Studies Fluorescent Probes Formulation Future G-Protein-Coupled Receptors Goals Headache Human Hyperplasia In Situ In Vitro Individual Inflammation Inflammatory Inflammatory Response Inhalation Interleukin-13 Interleukin-4 Interleukin-5 Lead Leucocytic infiltrate Leukocyte Elastase Leukotrienes Ligands Lung MAPK3 gene Measures Mediating Methods Modeling Mucous body substance Muscle relaxation phase Nasopharyngitis Nose Oral Oral Administration PAR-2 Receptor Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Population Principal Investigator Process Production Proteinase-Activated Receptors Pyroglyphidae Rattus Relaxation Respiratory Tract Infections Serine Protease Severities Signal Pathway Signal Transduction Small Business Technology Transfer Research Smooth Muscle Surface Symptoms Testing Therapeutic Time Transgenic Organisms Tryptase United States Universities Vertebral column Xolair adverse outcome airway hyperresponsiveness antagonist anti-IgE asthma exacerbation asthma model asthma prevention asthmatic beta-arrestin cytokine digital imaging drug development fungus human tissue improved in vivo inflammatory lung disease inhibitor interleukin-19 microscopic imaging montelukast mouse model neutrophil novel novel therapeutics pathogen peptidomimetics pharmacokinetics and pharmacodynamics phase 1 study pre-clinical preservation prevent programs receptor recruit response scaffold side effect small molecule standard of care

项目摘要

Lay Abstract: Asthma is a widely prevalent condition that affects 1 in 12 adults in the United States and an estimated 300 million individuals worldwide. Mild asthma is well controlled by current standard of care (SOC), including long-acting b-adrenergic receptor agonists, anti- leukotrienes and/or inhaled corticosteroids. As patients progress to severe disease add-on treatment options can include newer biologics/antibody treatments. While these treatments are useful for certain conditions, their application and known side effects limit their applicability resulting in 50% of asthmatics remaining untreated. There is a clear need for developing novel asthma drugs to treat this population. Protease-activated receptor-2 (PAR2) is a G-protein- coupled receptor activated by serine proteases released from asthma-inducing pathogens as well as by endogenous proteases associated with asthma inflammation. We have shown that PAR2 is a viable target for asthma drug development by identifyin two small molecule PAR2 antagonists, C391 and C781, that limit allergen-induced asthma indicators following direct nasal application in pre-clinical animal models. In this application we propose to characterize two novel PAR2 antagonists (C937 and C938) with improved pharmacodynamics and pharmacokinetics that could allow for novel PAR2-directed antagonism treatment following oral drug administration. Successful completion of the proposed feasibility studies (Phase I) will establish a novel drug lead for asthma and allow for development of a small business Phase 2 application that will include drug optimization and formulation, in vivo efficacy of lead compounds in allergen challenges of chronic exposure mouse models as well as larger animal asthma models (rats and dogs) and advanced in vivo PK studies. Our overall goal is to move these drug leads forward so that they can be tested (Clinical Phase I studies) and used in humans to control asthma.

摘要：哮喘是一种广泛流行的疾病，在美国，每 12 名成年人中就有 1 人患有哮喘各国以及全世界估计有 3 亿人。轻度哮喘可以得到很好的控制目前的护理标准（SOC），包括长效β-肾上腺素能受体激动剂、抗- 白三烯和/或吸入皮质类固醇。随着患者进展为严重疾病治疗选择可以包括更新的生物制剂/抗体治疗。虽然这些治疗方法是对于某些条件有用，它们的应用和已知的副作用限制了它们的适用性导致 50% 的哮喘患者仍未得到治疗。显然需要开发新颖的治疗这一人群的哮喘药物。蛋白酶激活受体 2 (PAR2) 是一种 G 蛋白偶联受体也被哮喘诱发病原体释放的丝氨酸蛋白酶激活如与哮喘炎症相关的内源性蛋白酶。我们已经证明 PAR2 通过鉴定两种小分子 PAR2 拮抗剂，成为哮喘药物开发的可行目标， C391 和 C781，限制直接鼻腔施用后过敏原诱发的哮喘指标临床前动物模型。在此应用中，我们建议表征两种新颖的 PAR2 拮抗剂（C937 和 C938）具有改善的药效学和药代动力学，可以允许在口服药物给药后进行新型 PAR2 定向拮抗治疗。成功完成拟议的可行性研究（第一阶段）将建立新的先导药物用于哮喘并允许开发小型企业第二阶段应用程序，其中包括药物优化和配方，先导化合物在过敏原挑战中的体内功效慢性暴露小鼠模型以及大型动物哮喘模型（大鼠和狗）和先进的体内 PK 研究。我们的总体目标是推动这些药物先导化合物的发展，以便它们能够可以进行测试（临床一期研究）并用于人类控制哮喘。