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

摘要：哮喘是一种广泛流行的疾病，在美国每12个成年人中就有1个受到影响。 全世界大约有3亿人。轻度哮喘可通过以下方法得到良好控制： 当前标准治疗（SOC），包括长效b-肾上腺素能受体激动剂、抗- 白三烯和/或吸入的皮质类固醇。随着患者病情进展至重度， 治疗选择可包括更新的生物制剂/抗体治疗。虽然这些治疗 对于某些情况有用，它们的应用和已知的副作用限制了它们的应用 导致50%的哮喘患者未得到治疗。显然需要开发新的 哮喘药物来治疗这一人群。蛋白酶激活受体-2（PAR 2）是一种G蛋白， 偶联受体也被哮喘诱导病原体释放的丝氨酸蛋白酶激活 如通过与哮喘炎症相关的内源性蛋白酶。我们已经证明，PAR 2 通过鉴定两种小分子PAR 2拮抗剂， C391和C781，在直接鼻腔应用后限制过敏原诱导的哮喘指标， 临床前动物模型。在本申请中，我们提出表征两种新的PAR 2 具有改善的药效学和药代动力学的拮抗剂（C937和C938）， 允许在口服药物给药后进行新的PAR 2定向拮抗治疗。 成功完成拟议的可行性研究（第一阶段）将建立一个新的药物领导 并允许开发小型企业第2阶段应用程序，其中包括 药物优化和制剂，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较大动物哮喘模型（大鼠和犬）， 先进的体内PK研究。我们的总体目标是推动这些药物线索向前发展， 可以测试（临床I期研究）并用于人类控制哮喘。

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.