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)每年影响约190,000名患者并导致约75,000人死亡 在美国，急性呼吸窘迫综合征的死亡率约为40%，并在幸存者中造成很大的发病率。呼吸性 病毒，包括流感和现在的严重急性呼吸综合征冠状病毒2(SARS-CoV-2)，是 ARDS的重要原因，治疗选择有限。退伍军人病患者群体有许多风险 ARDS预后不良的因素包括高龄、肥胖、高血压、糖尿病和慢性 肺病和心脏病。目前还没有被证实有效的药物治疗方法。 阿兹。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有丝分裂原- 具有抗炎和稳定内皮屏障活性的活化蛋白激酶(MAPK)抑制剂。 与传统的p38催化抑制剂相比，p38催化抑制剂可以阻断所有下游信号转导，包括抗- 炎症途径，我们的新化合物针对底物对接位置之一，因此仅 阻止某些依赖p38的进程。与我的合作调查员夏皮罗博士、麦克雷尔博士和 Fletcher，我们使用计算机辅助药物设计(CADD)来鉴定一种先导化合物，UM101，它能结合 P38A上靠近ED底物对接位置的口袋，并展示了独特的生物活性轮廓。我们 开发了第二代类似物SF7044，具有更好的溶解性和改善的内皮屏障- 具有稳定、抗炎和肺保护作用。我们目前正在与Gen1e Life合作 为这些化合物授予专利的Sciences，LLC完成了临床前测试，并开始 SF7044的临床试验。在我们目前的荣誉奖期间，我们确定和筛选了另外200名 使用改进的CADD策略，将目标定位到与UM101相同的底物对接位置的化合物。我们 鉴定了四个具有良好的内皮屏障稳定活性和P38A结合活性的新先导化合物 与UM101和SF7044相比，具有明显的抗炎作用，但溶解性较差。活体内 在小鼠模型上的测试将需要重新配制或化学修饰这些新的先导化合物以 提高溶解度(如UM101)。此次更新的总体目标是使用与 开发SF7044来设计、合成和表征四个新的第二代类似物 具有更好的活性和类药物性质的先导化合物。因为新的先导化合物有更大的 比UM101或SF7044更稳定的内皮活性和P38A结合我们预计将开发第二个 生成的类似物具有显著改善的肺保护活性。我们将利用CADD和Medical ALI的化学原理、蛋白质结合分析以及人细胞和小鼠模型： 1.设计和合成每种新发现的4种先导化合物至少20个类似物以改进 P38A结合特性和类药物特性。 2.分析第二代类似物的靶向结合和生物活性。 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的渗出期(内毒素/热疗)和纤维增生期(博莱霉素)。 4.评估新化合物的脱靶效果 在这项工作结束时，我们将开发出新的非催化的第二代类似物 P38α抑制剂在小鼠肺损伤模型中的有效性和安全性改善提供管道 在ARDS临床测试之前准备好进行高级临床前测试的新化合物。