A NOVEL GUT-RESTRICTED ARYL HYDROCARBON RECEPTOR AGONIST WITH ACTIVITY IN THE DEXTRAN SODIUM SULFATE COLITIS MURINE MODEL

Abstract BACKGROUND Patients with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) have decreased production of endogenous aryl hydrocarbon receptor (AhR) ligands in colon tissue. Activation of the AhR is a potential novel therapeutic target for ulcerative colitis and may play an important role in promoting immune homeostasis through increased IL-22 production, downregulation of proinflammatory mediators, and improved epithelial barrier function. Indigo naturalis, a botanical extract containing potent AhR agonists, has been effective for the treatment of moderate-to-severe and treatment-refractory ulcerative colitis in multiple clinical studies. The most potent AhR agonist in indigo naturalis is indirubin. OBJECTIVE The objective was to develop novel indirubin prodrugs that maximize local colonic delivery and minimize systemic exposure to reduce the risk of potential systemic side effects. RESULTS We developed a novel synthetic small molecule prodrug of indirubin that maximizes colonic exposure and minimizes systemic exposure. In a dextran sodium sulfate (DSS)-induced colitis murine model, oral administration of our lead prodrug significantly reduced Disease Activity Index and weight loss similar in magnitude to indirubin. The prodrug resulted in colon concentrations of indirubin that were over 100-fold greater than plasma concentrations, and low systemic organ exposure. CONCLUSION Azora’s novel indirubin prodrug enhanced colonic delivery of indirubin while maintaining minimal systemic exposure in a DSS colitis murine model and may reduce the risk of systemic side effects. This compound may be suitable for development as a first-in-class oral AhR agonist for the treatment of ulcerative colitis.