Nouveau benzo-mimetics of 17R-Resolvin D2 are potent resolution agonists for inflammation

The acute inflammatory response is a highly coordinated protective process governed by a superfamily of mediators termed specialized proresolving mediators. This includes the recently uncovered 17R-Resolvin D2 (17R-RvD2). We report 17R-RvD2 is rapidly metabolized and locally inactivated by human macrophages. An analog was prepared in a stereospecific synthesis. This benzo-17R-RvD2 resists rapid enzymatic inactivation and shared 17R-RvD2's pro-resolving actions enhancing human macrophage efferocytosis (pico-nanomolar). In peritonitis, benzo-17R-RvD2 (1 ng/mouse; 2.7 pmol) limited neutrophil infiltration >70%, reduced tumor necrosis factor alpha (TNF-α), and increased interleukin-1 (IL-1) receptor antagonist. The analog (1 nM) also enhanced >50% Escherichia coli killing by human leukocytes, equi-molar potent to 17R-RvD2. Benzo-17R-RvD2 (5 nM) reduced the area of human neutrophil swarms on zymosan-targeted chips >30%, without reducing potency of neutrophil swarms against live Candida clusters. Benzo-17R-RvD2 activated human-RvD2 receptor, EC₅₀ ∼1.5 nM, comparable to 17R-RvD2. This longer-acting benzo-17R-RvD2 stimulated critical events in resolution of inflammation, providing a manufacturable prototype for potent SPM mimetics.