Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome

开发新型第二代抗炎底物选择性 p38 MAP 激酶抑制剂治疗急性呼吸窘迫综合征

• 批准号: 10367545
• 负责人: JEFFREY D HASDAY
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367545
• 关键词: 2019-nCoV; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Affinity; Age; Anti-Inflammatory Agents; Antiinflammatory Effect; Aspartate; Award; Binding; Binding Proteins; Biological; Biological Assay; Biological Sciences; Bleomycin; Blood Vessels; COVID-19; COVID-19/ARDS; Catalytic Domain; Cell model; Cells; Cessation of life; Chemicals; Chronic lung disease; Clinic; Clinical Trials; Complication; Computer Assisted; Computers; Databases; Death Rate; Development; Diabetes Mellitus; Docking; Dose; Drug Design; Drug Kinetics; Effectiveness; Endothelium; Exhibits; Fever; Funding; Future; Generations; Glutamates; Goals; Heart Diseases; Human; Hypertension; Hyperthermia; In Vitro; Infection; Inflammation; Influenza; Injury; Lead; Legal patent; Lung; Maps; Maryland; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Modification; Molecular; Monkeys; Morbidity - disease rate; Mus; Obesity; Outcome; Pathogenicity; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacy Schools; Phase; Phosphotransferases; Plasma; Preclinical Testing; Preparation; Process; Program Development; Property; Protective Agents; Protein Kinase; Protein phosphatase; RPS6KA5 gene; Rattus; Research Personnel; Risk Factors; Safety; Services; Signal Transduction; Site; Solubility; Specificity; Surface Plasmon Resonance; Survivors; Testing; Therapeutic; Thrombin; Toxic effect; Universities; Veterans; Virus; Work; analog; aqueous; cytokine; design; disability; drug candidate; drug development; efficacy testing; epithelial injury; improved; in vivo; in vivo evaluation; inhibitor; kinase inhibitor; lung injury; mortality; mouse model; multimodality; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; patient population; protective effect; pulmonary artery endothelial cell; receptor; receptor binding; research clinical testing; respiratory virus; safety study; scaffold; screening; stress activated protein kinase; therapeutic candidate; therapeutic target

Acute Respiratory Distress Syndrome (ARDS) affects ~190,000 patients and causes ~75,000 deaths per year in the U.S.A. ARDS has a mortality rate of ~40% and causes significant morbidity in survivors. Respiratory viruses, including influenza and now Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), are important causes of ARDS with limited therapeutic options. The VA patient population has many of the risk factors for having poor outcomes with ARDS, including older age, obesity, hypertension, diabetes, and chronic lung and heart disease. There are no currently available pharmacologic therapies proven to be effective in ARDS. To address this need, we developed a novel class of substrate- and function-selective p38 mitogen- activated protein kinases (MAPK) inhibitors with anti-inflammatory and endothelial-barrier stabilizing activity. Compared with conventional p38 catalytic inhibitors that block all downstream signaling including anti- inflammatory pathways, our novel compounds target one of the substrate docking sites and therefore only block certain p38-dependent processes. Together with my co-investigators, Drs. Shapiro, MacKerell, and Fletcher, we used computer-aided drug design (CADD) to identify a lead compound, UM101, that binds a pocket near the ED substrate docking site on p38a and exhibits a unique profile of biological activities. We developed a second-generation analog, SF7044, with greater solubility and improved endothelial barrier- stabilizing, anti-inflammatory, and lung-protective activities. We are currently collaborating with Gen1e Life Sciences, LLC, which licensed the patents for these compounds, completed preclinical testing and began clinical testing of SF7044. During our current Merit Award, we identified and screened 200 additional compounds targeted to the same substrate docking site as UM101 using a refined CADD strategy. We identified four new lead compounds with superior endothelial barrier stabilizing activity and p38a-binding compared with UM101 and SF7044 and distinct anti-inflammatory effect profiles, but poor solubility. In vivo testing in a mouse model will require reformulation or chemical modification of these new lead compounds to improve solubility (like UM101). The overall objective of this renewal is to use the same strategy as used for development of SF7044 to design, synthesize, and characterize second-generation analogs of the four new lead compounds with improved activity and drug-like properties. Since the new lead compounds have greater endothelial-stabilizing activity and p38a-binding than either UM101 or SF7044 we expect to develop second- generation analogs with substantially improved lung-protective activity. We will utilize CADD and medicinal chemistry principles, protein binding assays and human cell and mouse models of ALI: 1. Design and synthesize at least 20 analogs of each the 4 newly discovered lead compounds to improve p38a-binding and drug-like properties. 2. Analyze the second-generation analogs for target binding and biological activities. 3. Analyze toxicity and effectiveness of the most active second-generation analogs in mouse models of the exudative (LPS/hyperthermia) and fibroproliferative (bleomycin) phases of ARDS. 4. Evaluate new compounds for off-target effects At the conclusion of this work, we will have developed second generation analogs of novel non-catalytic p38α inhibitors with improved efficacy and safety profiles in mouse lung injury models to provide a pipeline of new compounds that are ready for advanced preclinical testing prior to clinical testing in ARDS.

急性呼吸窘迫综合征（ARDS）影响约190,000名患者，每年约75,000例死亡 在美国，ARDS的死亡率约为40％，并在生存中引起明显的发病率。呼吸道 病毒，包括影响力和现在严重的急性呼吸综合症冠状病毒-2（SARS-COV-2） 具有有限治疗选择的ARD的重要原因。 VA患者人群有许多风险 ARD的结果不佳的因素，包括年龄较大，肥胖，高血压，糖尿病和慢性 肺和心脏病。目前尚无可用的药理学疗法可有效 ARDS。为了满足这一需求，我们开发了一类新的底物和功能选择性p38丝裂原 - 活化的蛋白激酶（MAPK）抑制剂具有抗炎和内皮栏稳定活性。 与传统的p38催化抑制剂相比，该抑制剂阻止了所有下游信号传导 炎症途径，我们的新颖化合物靶向底物对接位点之一，因此仅针对 阻止某些依赖P38的过程。以及我的共同研究者Drs。 Shapiro，Mackerell和 弗莱彻（Fletcher 在p38a上的ED底物对接场附近的口袋，展示了生物活动的独特特征。我们 开发了第二代类似物SF7044，具有更大的溶解度和改善的内皮屏障 - 稳定，抗炎和肺部保护活动。我们目前正在与Gen1e Life合作 获得这些化合物专利的Sciences，LLC完成了临床前测试并开始 SF7044的临床测试。在当前的优异奖中，我们确定并筛选了200个 使用精制的CADD策略针对与UM101相同的底物对接位点的化合物。我们 确定了具有上皮屏障稳定活性和p38a结合的四种新铅化合物 与UM101和SF7044以及明显的抗炎作用曲线相比，溶解度差。体内 在鼠标模型中测试将需要对这些新铅化合物进行重新调整或化学修饰 提高溶解度（例如UM101）。这种续签的总体目标是使用与使用相同的策略 SF7044的开发以设计，合成和表征这四个新的第二代类似物 铅化合物具有改善的活性和类似药物的特性。由于新的铅化合物具有更大的 与UM101或SF7044相比，内皮稳定活性和p38a结合，我们期望发展第二 具有显着改善肺部保护活性的生成类似物。我们将利用CADD和医学 化学原理，蛋白质结合测定以及ALI的人类细胞和小鼠模型： 1。设计和合成至少20种新发现的铅化合物的20个类似物 p38a结合和类似药物的特性。 2。分析目标结合和生物学活性的第二代类似物。 3。分析最活跃的第二代类似物在小鼠模型中的毒性和有效性 ARDS的渗出症（LPS/高温）和纤维增生性（博来霉素）阶段。 4。评估新化合物的脱靶效果 在这项工作的结论中，我们将开发出新型非催化的第二代类似物 在小鼠肺损伤模型中具有提高效率和安全性的p38α抑制剂以提供管道 在ARDS进行临床测试之前准备进行高级临床前测试的新化合物。