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人受到影响 据估计，全世界有3亿人。轻度哮喘得到了很好的控制 目前的护理标准(SOC)，包括长效b-肾上腺素能受体激动剂，抗- 白三烯和/或吸入皮质类固醇。随着患者病情加重，病情加重 治疗选择可以包括较新的生物制剂/抗体治疗。虽然这些治疗方法是 在某些情况下有用，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。发展小说显然是有必要的 治疗这一人群的哮喘药物。蛋白水解酶激活受体-2(PAR2)是一种G蛋白。 哮喘病原体释放的丝氨酸蛋白酶激活的偶联受体 由于内源性蛋白水解酶与哮喘炎症有关。我们已经证明了PAR2 通过鉴定两种小分子PAR2拮抗剂是哮喘药物开发的一个可行的靶点， C391和C781，限制直接滴鼻后过敏原诱发哮喘的指标 临床前动物模型。在本申请中，我们建议表征两个新PAR2 拮抗剂(C937和C938)具有改进的药效学和药代动力学，可以 允许在口服给药后进行新的PAR2导向的拮抗治疗。 成功完成拟议的可行性研究(第一阶段)将建立一种新的药物领先地位 用于哮喘，并允许开发小型企业第二阶段应用程序，该应用程序将包括 药物优化和配方，体内先导化合物的疗效在变应原挑战 慢性暴露的小鼠模型以及更大的动物哮喘模型(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线索向前推进，以便他们 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.