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

 描述（由申请人提供）：本项目的目的是开发一种吸入性组合c-kit/PDGFR抑制剂，用于治疗哮喘。哮喘是一种以气道高反应性和气道重塑为特征的慢性炎症性疾病。哮喘的一个关键潜在机制涉及辅助性T细胞2型（Th 2）淋巴细胞的活化，产生过敏原特异性IgE，以及肥大细胞和嗜酸性粒细胞的活化。在严重哮喘中，随着中性粒细胞和组织损伤的增加，涉及Th 2、Th 1和Th 17细胞的更复杂的表型发展。杯状细胞增生和粘液产生增加是涉及慢性和急性哮喘恶化的另一个因素。气道平滑肌细胞（ASM）的肥大和增生、血管生成和细胞外基质（ECM）沉积增加导致管道气道的慢性重塑。尽管目前有可用的治疗方法，但哮喘仍然是一种发病率很高的疾病。虽然大多数患者可以有效地管理与抗炎药和支气管扩张剂，一个显着的子集继续有症状，从而导致高医疗保健费用，很少，死亡。酪氨酸激酶抑制剂治疗哮喘的潜在用途越来越受到关注。与哮喘发病机制和进展有关的激酶途径包括EGFR、c-kit、PDGFR和VEGFR。Pulmokine已经发明了一系列对c-kit和PDGFR具有高效力的组合酪氨酸抑制剂。通过吸入递送API，我们希望增加功效并减少全身副作用。待开发的主要候选药物均显示出在纳摩尔范围内抑制c-kit、PDGFR α和PDGFR β的IC 50值。在目标1中，我们将开发吸入用候选API的临床前制剂。将合成三种候选药物（PK 1019、1035和1036）并配制成喷雾干燥粉末。先导候选物在100%乙醇至50%乙醇中高度可溶。因此，DSPC或亮氨酸可用作辅料。喷雾干燥参数将根据关键热力学参数进行优化。分析方法开发将包括HPLC或LC/MS/MS。将对喷雾干燥分散剂的粒度分布（NGI级联冲击）、含水量（TGA）、玻璃化转变温度（调制差示扫描量热法，mDSC）、X射线粉末衍射（XRPD）和SEM（形态学）进行表征。在Aim 2中，我们将在哮喘大鼠模型中进行药代动力学和临床前疗效研究。将研究两种配制成喷雾干燥粉末的候选药物，以确定药代动力学并确定配制的候选药物的效果。在重复暴露OVA模型中，将检测乙酰甲胆碱反应。将通过组织形态计量学评估气道平滑肌细胞（ASM）面积、杯状细胞增生和支气管周围纤维化。还将测量上皮变化和炎症特征。将通过其他器官（包括心脏、肝脏、肾脏和脑）的组织学检查评估非GLP毒性。在I期研究中证明可行性后，我们将进入II期SBIR研究，该研究将在首次人体临床试验之前进行所需的临床前研究。这项研究的结果可能会导致一种新的哮喘治疗方法，从而使美国和其他国家的患者和社会受益。

 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.