A novel JAK inhibitor for the treatment of pulmonary arterial hypertension

描述(申请人提供)：肺动脉高压(PAH)是一种罕见的疾病，具有很高的发病率和死亡率。这项建议的目的是开发一种新的JAK1/JAK2联合抑制剂或更具选择性的JAK2抑制剂，用于PAH，将通过吸入给药。主要候选药物将为导致PAH的两个关键病因提供治疗：血管收缩和病理性细胞增殖。由于PAH涉及肺小动脉床，直接吸入给药将改善治疗窗口：即增加疗效，并减少全身副作用。该方法将包括以下步骤：1)制定可用于雾化的候选药物，并利用SPECT、伽玛闪烁成像和三维计算机断层扫描确定吸入气雾剂的呼吸沉积模式。2)确定候选药物的吸入和沉积质量以及候选药物的药代动力学分布。3)确定先导候选药物对两种PAH模型的疗效和治疗窗口。该项目的结果将导致制定用于人类和IND使能研究的主要候选者之一。这种新的治疗方法可以降低PAH的发病率和死亡率，从而造福于患者和社会。 公共卫生相关性：肺动脉高压是一种发病率和死亡率都很高的破坏性疾病。该项目与公众健康相关，因为它最终将导致一种治疗肺动脉高压的新方法。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a rare disease associated with high morbidity and mortality. The purpose of this proposal is to develop a novel combined JAK1/JAK2 inhibitor or more selective JAK2 inhibitor for PAH that will be delivered by inhalation. The lead drug candidates will provide a treatment for the two key etiologic factors that lead to PAH: vasoconstriction and pathologic cellular proliferation. Because PAH involves the pulmonary arteriolar bed, direct delivery of the drug by inhalation will improve the therapeutic window: i.e., increase efficacy, and decrease systemic side effects. The approach will consist of the following steps: 1) Formulate the drug candidates for aerosolization and determine the respiratory deposition pattern of inhaled aerosol with SPECT gamma scintigraphy and three dimensional computed tomography. 2) Determine the inhaled and deposited mass of the drug candidates and pharmacokinetic distribution of the drug candidates. 3) Determine the efficacy and therapeutic window of lead drug candidates in 2 models of PAH. The results of this project will lead to formulation of one of the lead candidates for use in humans and IND enabling studies. This new treatment could reduce the morbidity and mortality of PAH and thereby benefit patients and society. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a devastating disease with a high morbidity and mortality. This project is relevant to public health because it will ultimately lead to a new treatment for pulmonary arterial hypertension.