A PDGFR inhibitor for the treatment of pulmonary arterial hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种具有高发病率和死亡率的毁灭性疾病。本提案的目的是开发一种新型的高选择性血小板衍生生长因子受体（PDGFR）抑制剂，用于PAH的吸入递送。通过PDGFR信号传导导致平滑肌细胞增殖，从而促进PAH的发展。PDGFR抑制剂伊马替尼在一些患者中显示出治疗PAH的疗效。然而，也有人担心伊马替尼的脱靶效应，因为它也抑制另一种名为Abl的激酶。在这个提议中开发的PDGFR抑制剂比伊马替尼更具选择性，并且不抑制Abl。本提案将开发这些用于肺直接输送的新型抑制剂。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PAH模型中的疗效和治疗窗口期。候选药物对肺动脉高压的影响将通过肺动脉压的连续遥测监测来测量。研究药物对右心室功能的影响将通过超声心动图和一种新的导纳技术来评估。将进行组织学检查，以评估研究药物对多环芳烃相关肺部病理的影响。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 devastating disease associated with high morbidity and mortality. The purpose of this proposal is to develop a novel highly selective platelet derived growth factor receptor (PDGFR) inhibitor for PAH that will be delivered by inhalation. Signaling through the PDGFR leads to smooth muscle cell proliferation which contributes to the development of PAH. The PDGFR inhibitor imatinib has shown efficacy in treating PAH in some patients. However, there are some concerns about off-target effects of imatinib because it also inhibits another kinase called Abl. The PDGFR inhibitors to be developed in this proposal are more selective than imatinib and do not inhibit Abl. This proposal will develop these novel inhibitors for direct pulmonary delivery. 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 a model of PAH. The effect of the drug candidates on pulmonary hypertension will be measured by continuous telemetry monitoring of pulmonary artery pressure. The effect of study drug on right ventricular function will be evaluated with echocardiography, and a new admittance technology to generate pressure-volume loops. Histology will be performed to evaluate the effect of the study drugs on the pulmonary pathology associated with 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.