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：哮喘是一种普遍存在的疾病，影响了曼联十二名成年人中的1个全球估计和大约3亿个人。轻度哮喘受到很好的控制当前的护理标准（SOC），包括长效B-肾上腺素能受体激动剂，抗白细胞和/或吸入的皮质类固醇。随着患者的进展到严重疾病附加治疗方案可以包括新的生物制剂/抗体治疗。虽然这些治疗是对于某些条件，其应用和已知副作用限制了其适用性导致50％的哮喘患者仍未治疗。显然需要开发小说哮喘药物治疗这一人群。蛋白酶激活的受体2（PAR2）是G蛋白 - 还由从哮喘诱导病原体释放的丝氨酸蛋白酶激活的耦合受体如与哮喘炎症相关的内源性蛋白酶。我们已经证明了PAR2 是通过识别两个小分子PAR2拮抗剂来实现哮喘药物发育的可行靶标， C391和C781，限制了过敏原诱导的哮喘指标，直接鼻腔施用临床前动物模型。在此应用中，我们建议表征两个新型PAR2 具有改进的药效和药代动力学的拮抗剂（C937和C938）可以口服药物给药后允许新的PAR2定向拮抗治疗。成功完成拟议的可行性研究（I阶段）将建立新的药物铅哮喘并允许开发小型企业2应用程序，其中包括药物优化和配方，铅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较大的动物哮喘模型（大鼠和狗）和先进的体内PK研究。我们的总体目标是将这些药物推向前进，以便它们可以测试（I期研究），并用于人类控制哮喘。