Development of Small Molecule Antagonists of PAR-2 for treatment of asthma

摘要：目前的哮喘治疗主要是通过以下方法减少病情加重： 直接治疗气道炎症。虽然在一部分患者中取得了成功， 急性加重仍然是发病和死亡的重要原因， 损伤、肺功能下降和死亡。更严重的哮喘患者的病情加重是 特别值得关注的是，在美国，医疗保健成本和生产力损失每年高达210亿美元 年度医疗保健支出。因此，迫切需要开发新的疗法， 用于治疗哮喘。蛋白酶激活受体-2（PAR-2）是一种G蛋白偶联的 由诱发哮喘的过敏原释放的丝氨酸蛋白酶激活的受体（例如德国 蟑螂、尘螨和真菌互隔交链孢菌），以及肥大细胞类胰蛋白酶， 人气道胰蛋白酶、膜结合TMPRSS2和嗜中性粒细胞弹性蛋白酶。激活PAR-2 通过过敏原或激动剂导致复杂的细胞信号传导（b-抑制蛋白和Gaq-Ca2+）， 有助于生理反应。使用转基因动物，我们已经证明 PAR-2/b-抑制蛋白信号传导可导致有害结果（例如，细胞因子产生， 白细胞浸润、上皮增生、粘液分泌和气道高反应性） 而PAR-2/Gaq-Ca 2+途径可能是有益的（例如，支气管松弛）。我们长达十年的 配体鉴定程序已经导致了一些最有效和选择性的PAR-2 激动剂和第一个完整的PAR-2拮抗剂C391。此外，我们已经证明C391可以 减少有害物质A。在临床前模型中观察到的alternata诱导的哮喘指标。最近， 我们已经鉴定了几种新的小分子PAR-2拮抗剂，包括β-抑制蛋白， 选择性拮抗剂C781是一个有希望的候选人，只针对有害作用 气道中的PAR-2我们的中心假设是PAR-2的b-抑制蛋白选择性拮抗作用 将减少过敏原诱导的哮喘指标，导致恶化。的第一个目标 这个I期STTR提案是为了证明第一个小分子偏向的拮抗PAR， 2配体（C781）可有效限制临床前小鼠中变应原诱导的哮喘指标 模型第二个目标是修饰C391和C781以用于肺特异性靶向， 保留/改善其PAR-2拮抗功能。我们的公司PARMedics 基于这样的原则，我们可以创建自定义修改与改进 这类新型哮喘的药代动力学特性和稳定性 治疗学

ABSTRACT: Current treatments for asthma largely are aimed at reducing exacerbations by directly treating airway inflammation. While successful in a subset of patients, asthma exacerbations remain a significant cause of morbidity and mortality and can result in airway injury, lung function decline and death. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. Thus, there is a critical need to develop new therapies to be used in the treatment of asthma. Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated by serine proteases released from asthma-inducing allergens (e.g. German cockroach, dust mites and the fungus Alternaria alternata), as well as by mast cell tryptase, human airway trypsin, membrane bound TMPRSS2 and neutrophil elastase. Activated of PAR-2 via allergens or agonists results in complex cellular signaling (b-arrestin and Gaq-Ca2+) that contribute to the physiological response. Using genetically modified animals, we have shown that PAR-2/b-arrestin signaling can lead to detrimental outcomes (e.g., cytokine production, leukocyte infiltration, epithelial hyperplasia, mucus secretion and airway hyperresponsivenes) while PAR-2/ Gaq-Ca2+ pathways can be beneficial (e.g., broncho-relaxation). Our decade-long ligand-identification program has resulted in some of the most potent and selective PAR-2 agonists and the first full PAR-2 antagonist, C391. Further, we have shown that C391 can reduce the detrimental A. alternata-induced asthma indicators in pre-clinical models. Recently, we have identified several novel small molecule PAR-2 antagonists, including the b-arrestin- selective antagonist C781 that is a promising candidate for targeting only the detrimental effects of PAR-2 in the airway. Our central hypothesis is that b-arrestin-selective antagonism of PAR-2 will reduce allergen-induced asthma indicators that lead to exacerbations. The first objective of this Phase I STTR proposal is to demonstrate the first small molecule biased antagonistic PAR- 2 ligand (C781) can effectively limit allergen-induced asthma indicators in a pre-clinical mouse model. The second objective is to modify C391 and C781 for pulmonary-specific targeting while retaining/improving on their PAR-2 antagonistic function. Our company, PARMedics, was founded on the principle that we can create custom modifications with improved pharmacokinetic properties and stability for the development of this new class of asthma therapeutics.