Development of inhaled, dual EP2/4 receptor agonists for the treatment of idiopathic pulmonary fibrosis

该项目旨在提供用于治疗特发性肺纤维化（IPF）的新型候选药物，IPF是一种衰弱和致命的疾病，几乎没有治疗选择。IPF是一种慢性、进行性和致死性肺部疾病，其特征是肺部过度瘢痕形成，这一过程称为纤维化。纤维化导致气道变硬，使肺部更难正常充气和发挥功能，导致呼吸急促。IPF患者的症状会随着时间的推移而恶化，导致无法进行我们许多人认为理所当然的活动，包括日常任务，如洗涤和穿衣，并最终因窒息而死亡。我们目前还不了解导致纤维化的过程，因此开发治疗IPF的高效药物仍然难以捉摸。IPF是一种复杂的疾病，准确诊断具有挑战性。目前的估计表明，英国每10万人中约有50人被诊断为IPF，每年约有40，000名患者死亡。从确诊开始，患者的平均生存时间仅为3年，但患者之间的进展速度差异很大，这意味着约20%的患者存活超过5年。虽然我们不清楚IPF的确切原因，但很可能是化学、颗粒或病毒损伤肺内膜的结果。这导致肺部发生一连串事件，这些事件是由肺部自然产生的物质过度产生引起的，这些物质通常负责刺激生长。这些物质的非自然发生水平导致失控的伤口愈合，导致肺部疤痕。目前用于IPF的药物已从癌症治疗中重新利用。它们在减轻症状方面很差，并且有使人衰弱的副作用。这些口服药物会给全身带来副作用，如无法忍受的腹泻。这些症状非常严重，以至于许多患者选择停止服用这些药物，因为他们所经历的毁灭性副作用超过了对他们健康的好处。显然，我们需要新的、更有效和更安全的药物来治疗IPF。我们已经确定了一种治疗IPF的新方法。首先，我们希望激活一种途径，以抵消IPF中涉及的许多过程，无论是哪种物质引起的根本问题。我们感兴趣的靶点是前列腺素E2受体亚型2和4（EP 2和EP 4受体）。我们已经确定了激活这些受体的新型化合物，并产生了数据，证明这些化合物能够有力地抑制IPF中涉及的关键细胞过程，因此有可能治疗这种使人衰弱的疾病。我们正在开发这些药物，使用喷雾器，类似于其他肺部疾病，如哮喘。这将使我们能够将药物直接输送到需要它们的肺部，而不会到达身体其他部位，因为它们可能会造成不必要的影响。虽然雾化目前的治疗方法可以改善他们的全身副作用，但这不会改善现有药物的不良临床效果。该项目由诺丁汉大学的研究人员设计和提交，他们在制造肺部疾病药物方面具有重要的专业知识，已经成功地将哮喘和慢性阻塞性肺疾病（COPD）的新药推向市场，并且之前已经从现有的MRC-DPFS资金中确定了早期药物样候选物。我们的目标是在这些成功的基础上，为IPF患者开发一种新的、安全有效的治疗方法。

This project aims to deliver novel drug candidates for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a debilitating and fatal disease for which few treatment options are available. IPF is a chronic, progressive and fatal lung disease that is characterised by excessive scarring of the lung, a process known as fibrosis. Fibrosis leads to stiffening of the airways and makes it harder for the lungs to inflate and function normally, resulting in shortness of breath. Patients with IPF experience worsening symptoms over time that lead to the inability to undertake activities that many of us take for granted, including daily tasks such as washing and dressing, and ultimately death through suffocation. We do not currently understand the processes that lead to fibrosis, therefore the development of highly effective medicines to treat IPF remains elusive.IPF is a complex disease and accurate diagnosis is challenging. Current estimates state that approximately 50 per 100,000 people in the UK have an IPF diagnosis, with about 40,000 patients dying per year. The average survival time of patients is only 3 years from time of diagnosis, however rate of progression varies greatly amongst patients meaning about 20% of people with the disease survive for more than 5 years.Although we don't understand exactly what causes IPF, it is likely to be the result of damage to the lining of the lung, either by chemical, particulate or viral insults. This leads to a cascade of events in the lungs which are caused by the over-production of naturally occurring substances in the lung, which would normally be responsible for stimulating growth. The unnaturally occurring levels of these substances results in out of control wound healing that leads to the scarring of the lungs. Current medicines for IPF have been repurposed from cancer treatments. They are poor at reducing symptoms and have debilitating side effects. These oral medications dose the whole body, causing widespread side effects such as intolerable diarrhoea. These symptoms are so severe that many patients choose to stop taking these medicines, as the benefits to their health are outweighed by the devastating side effects they experience. There is clearly a need for new, more effective and safer medicines to treat IPF.We have identified a novel approach to treat IPF. Firstly, we wish to activate a pathway that will counteract many of the processes involved in IPF, regardless of which substance is causing the underlying problem. The targets we are interested in are the prostaglandin E2 receptor subtypes 2 and 4 (EP2 and EP4 receptors). We have identified novel compounds that activate these receptors, and generated data demonstrating these compounds are able to robustly inhibit key cellular processes involved in IPF, and therefore have the potential to treat this debilitating disease. We are developing these medicines to be taken using a nebuliser, similar to other lung diseases like asthma. This will allow us to deliver our medicines directly to the lung where they are needed, without reaching the rest of the body where they may cause unwanted effects. Although nebulising current therapies would improve their whole body side effect profiles, this won't improve the poor clinical effect of existing medicines.This project has been designed and submitted by researchers at the University of Nottingham who have significant expertise in making drugs for lung diseases, having successfully brought new drugs to market for asthma and chronic obstructive pulmonary disease (COPD), and have previously identified early drug-like candidates from existing MRC-DPFS funding. Our aim is to build on these successes and develop a novel, safe and effective therapy for IPF patients.