A novel JAK inhibitor for the treatment of pulmonary arterial hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种发病率和死亡率高的罕见疾病。本提案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，用于吸入输送PAH。主要候选药物将为导致多环芳烃的两个关键病因提供治疗：血管收缩和病理性细胞增殖。由于多环芳烃累及肺小动脉床，直接吸入给药将改善治疗窗口期，即提高疗效，减少全身副作用。该方法将包括以下步骤：1)制定雾化候选药物，并使用SPECT伽玛闪烁成像和三维计算机断层扫描确定吸入气溶胶的呼吸沉积模式。2)测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)确定候选先导药物在2种PAH模型中的疗效和治疗窗口期。该项目的结果将导致制定用于人类和IND支持研究的主要候选药物之一。这种新的治疗方法可以降低PAH的发病率和死亡率，从而使患者和社会受益。

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.