A PDGFR inhibitor for the treatment of pulmonary arterial hypertension

用于治疗肺动脉高压的PDGFR抑制剂

• 批准号: 7908994
• 负责人: LAWRENCE S. ZISMAN
• 金额: $ 35.1万
• 依托单位: PULMOKINE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908994
• 关键词: Address; Adverse effects; Aerosols; Affect; Agonist; Alveolar; Animal Model; Area; Beds; Breathing; Cardiac Output; Cardiopulmonary; Case Study; Cell Proliferation; Chemicals; Chronic Myeloid Leukemia; Clinical Trials; Deposition; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Echocardiography; Goals; Histology; Human; Imatinib; Lead; Lesion; Lung; Measures; Modeling; Monitor; Monocrotaline; Morbidity - disease rate; Particle Size; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Play; Pneumonectomy; Public Health; Pulmonary Hypertension; Pulmonary Pathology; Pulmonary artery structure; Radionuclide Imaging; Rattus; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Refractory; Right Ventricular Function; Role; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Societies; Staging; Structure of parenchyma of lung; Technology; Telemetry; Therapeutic; Time; Toxic effect; Treatment Efficacy; Tyrosine Kinase Inhibitor; United States; X-Ray Computed Tomography; arteriole; drug candidate; drug inhalation; hemodynamics; improved; inhibitor/antagonist; innovation; meetings; mortality; novel; patient population; pressure; public health relevance; pulmonary arterial hypertension; respiratory; single photon emission computed tomography

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.

描述（由申请人提供）：肺动脉高压（PAH）是一种与高发病率和死亡率相关的毁灭性疾病。该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，将通过吸入给药。通过PDGFR的信号传导导致平滑肌细胞增殖，这有助于PAH的发展。PDGFR抑制剂伊马替尼在治疗一些患者的PAH方面显示出疗效。然而，有一些关于伊马替尼的脱靶效应的担忧，因为它也抑制另一种激酶，称为PDGFR抑制剂，在这个提案中开发的PDGFR抑制剂比伊马替尼更具选择性，不抑制PDGFR，这个提案将开发这些新的抑制剂，用于直接肺部给药。由于PAH涉及肺小动脉床，通过吸入直接递送药物将改善治疗窗：即，增加功效并减少全身副作用。该方法将包括以下步骤：1）配制用于雾化的候选药物，并用SPECT γ射线照相术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)在PAH模型中确定先导候选药物的疗效和治疗窗。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新的导纳技术来评估，以生成压力-容积环。将进行组织学检查，以评价研究药物对PAH相关肺病理学的影响。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。 公共卫生相关性：肺动脉高压是一种具有高发病率和死亡率的毁灭性疾病。该项目与公共卫生有关，因为它最终将导致肺动脉高压的新治疗方法。