Discovery of Safe COX‐2 Inhibitors: Achieving Reduced Colitis Side Effects through Balanced COX Inhibition

Abstract The severe adverse effects associated with imbalanced cyclooxygenase‐2 (COX‐2) inhibition continue to pose significant challenges in the development of contemporary anti‐inflammatory drugs. In recent years, the approach to COX‐2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX‐2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX‐2 and constitutive cyclooxygenase‐1 (COX‐1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX‐2 inhibitors. As part of our ongoing research into the discovering novel and safer COX‐2 inhibitors, we reported herein a highly potent and balanced COX‐2 inhibitor 21 d (IC 50 value=1.35 μM, selectivity profile (IC 50 (COX‐1)/IC 50 (COX‐2)=22.34)). In vivo assays demonstrated that 21 d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)‐induced acute colitis.