Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases

Soluble epoxide hydrolase (sEH) has been identified as
an attractive
target for anti-inflammatory drug design in recent years. Picomolar
level compound G1 against sEH was obtained by introducing
the hydrophilic group homopiperazine and hydrophobic fragment propionyl
onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding
rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice,
ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil
infiltration, and increased the survival time of C57BL/6 mice in a
lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression
levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM),
IL-6, MCP-5, and tumor necrosis factor α (TNF-α) were
measured by Western blot or enzyme-linked immunosorbent assay (ELISA),
with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the
treatment of inflammation-induced diseases such as arthritis, acute
pancreatitis, and sepsis.