We have previously identified a small three-ring molecule, UM101, targeted to the ED substrate-docking domain of p38alpha MAPK. UM101 modified p38alpha/MK2 signaling, stabilized endothelial barrier and reduced expression of proinflammatory genes. A next-generation analog with modifications on the first and third ring, Gen-1124, has improved anti-inflammatory and endothelial barrier-stabilizing activity, is lung protective in mouse models of influenza and ARDS, and is currently in a Phase II clinical trial in ARDS. To develop additional therapeutic candidates, we designed and synthesized UM101 analogs with modifications on the middle ring and tested the novel compounds for endothelial barrier- stabilizing and anti-inflammatory activity.