A novel inhaled c-kit/PDGFR inhibitor for the treatment of asthma

一种用于治疗哮喘的新型吸入性 c-kit/PDGFR 抑制剂

• 批准号: 9139718
• 负责人: LAWRENCE S. ZISMAN
• 金额: $ 33.73万
• 依托单位: PULMOKINE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-07 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139718
• 关键词: Acute; Address; Adverse effects; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Brain; Breathing; Bronchodilator Agents; Cells; Cessation of life; Characteristics; Chronic; Clinical Trials; Complex; Country; Deposition; Differential Scanning Calorimetry; Disease; Dose; Drug Kinetics; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Ethanol; Excipients; Extracellular Matrix; Feasibility Studies; Fibrosis; Formulation; Glass; Goblet Cells; Grant; Health Care Costs; Heart; High Pressure Liquid Chromatography; Histologic; Human; Hyperplasia; Hypertrophy; IgE; Inflammatory; Injury; Interleukin-13; Interleukin-4; Interleukin-6; KDR gene; Kidney; Lead; Leucine; Liver; Lymphocyte; Measures; Modeling; Morbidity - disease rate; Morphology; Mucous body substance; Organ; PDGFRB gene; PI3K/AKT; Particle Size; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Powder Diffraction; Powder dose form; Prevalence; Production; Proto-Oncogene Protein c-kit; Public Health; Rattus; Roentgen Rays; Series; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Societies; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; Transition Temperature; Tyrosine; Tyrosine Kinase Inhibitor; United States; Water; airway hyperresponsiveness; angiogenesis; clinical efficacy; drug candidate; eosinophil; improved; inflammatory marker; inhibitor/antagonist; interest; kinase inhibitor; liquid chromatography mass spectrometry; methacholine; method development; nanocrystal; nanomolar; neutrophil; novel; particle; phase II trial; pre-clinical; preclinical study; public health relevance; respiratory smooth muscle; response

 DESCRIPTION (provided by applicant): The purpose of this project is to develop an inhaled combined c-kit/PDGFR inhibitor as a treatment for asthma. Asthma is a chronic inflammatory disease characterized by airway hyper-responsiveness, and remodeling. A key underlying mechanism of asthma involves activation of T-helper type 2 (Th2) lymphocytes with production of allergen specific IgE, and activation of mast cells and eosinophils. In severe asthma a more complex phenotype involving Th2, Th1, and Th17 cells develops with increased neutrophils and tissue injury. Goblet cell hyperplasia and increased mucus production is another factor involved in chronic and acute asthma exacerbation. Hypertrophy and hyperplasia of airway smooth muscle cells (ASM), angiogenesis, and increased deposition of extracellular matrix (ECM), lead to chronic remodeling of the conduit airway. Despite currently available treatments, asthma remains a disease of significant morbidity. While most patients can be effectively managed with anti-inflammatory drugs and bronchodilators, a significant subset continue to be symptomatic with resultant high health care costs and, rarely, death. There is a growing interest in the potential use of tyrosine kinase inhibitors to treat asthma. Kinase pathways implicated in the pathogenesis and progression of asthma include EGFR, c-kit, PDGFR, and VEGFR. Pulmokine has invented a series of combined tyrosine inhibitors with high potency against c-kit and PDGFR. By delivering the API by inhalation we hope to increase efficacy and decrease systemic side-effects. The lead candidates to be developed all show IC50 values for inhibition of c-kit, PDGFR alpha, and PDGFRbeta in the nanomolar range. In Aim1 we will develop pre-clinical formulations of the candidate APIs for inhalation. Three drug candidates (PK1019, 1035, and 1036) will be synthesized and formulated as a spray dry powder. The lead candidates are highly soluble in 100% ethanol down to 50% ethanol. Therefore, DSPC or leucine may be used as excipients. Spray dry parameters will be optimized according to key thermodynamic parameters. Analytic method development will consist of HPLC or LC/MS/MS. The SDDs will be characterized, for particle size distribution (NGI cascade impaction), water content (TGA), glass transition temperature (modulated differential scanning calorimetry, mDSC), X ray powder diffraction (XRPD), and SEM for morphology. In Aim2 we will perform pharmacokinetic and pre-clinical efficacy studies in a rat model of asthma. Two drug candidates formulated as spray dry powders will be studied to determine pharmacokinetics and determine effect of formulated drug candidate. In the repeat exposure OVA model, methacholine response will be tested. Airway smooth muscle cell (ASM) area, goblet cell hyperplasia, and peribronchial fibrosis will be assessed by histomorphometry. Epithelial changes and an inflammatory profile will also be measured. Non-GLP toxicity will be assessed by histologic examination of other organs including heart, liver, kidney, and brain. After demonstrating feasibility in phase I we will then o on to a phase II SBIR study that will undertake the preclinical studies required prior to testing i a first in human clinical trial. The results of this study could lead to a new treatment for asthma and thereby benefit patients and society in the United States and other countries.

 描述（通过应用程序证明）：这是哮喘的吸收c-kit/pdgfr抑制剂的目的。 ）在严重的哮喘中产生特异性IgE的淋巴细胞。 E导向呼吸道。 -KIT，PDGFR和VEGFR的结合金的合并酪氨酸抑制剂与C-KIT和PDGFR的效力高。对于c-kit，pdgfr alpha和pdgfrbeta的纳莫尔范围，我们将综合候选者的纳莫尔范围。在100％的乙醇中，DSPC或亮氨酸可以使用C参数。 ，水含量（TGA），玻璃过渡温度，MDSC），X射线粉末衍射（XRPD）和SEM用于AIM2中的形态。进行研究以确定候选药物的药代动力学在重复的OVA模型中测量的THEIS研究的结果可能会导致针对哮喘的新疗法，在这里使美国和其他国家的患者和社会受益。