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-...