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: 10535453
• 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/10535453
• 关键词: 2019-nCoV; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Affect; Affinity; 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; Collaborations; Complication; Computer Assisted; Computers; Databases; Death Rate; Development; Diabetes Mellitus; Docking; Dose; Drug Design; Drug Kinetics; Effectiveness; Endothelium; Exhibits; Fever; Formulation; Funding; Future; Generations; Glutamates; Goals; Heart Diseases; Human; Hypertension; Hyperthermia; In Vitro; Induced Hyperthermia; Infection; Inflammation; Inflammatory; Influenza; Injury; Lead; Legal patent; Licensing; 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; 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; candidate identification; cytokine; design; disability; drug candidate; drug development; efficacy testing; epithelial injury; human old age (65+); 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; pharmacologic; phosphoproteomics; 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19万患者，导致约7.5万人死亡