Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases.
J Med Chem
; 66(4): 2979-3009, 2023 02 23.
Article
em En
| MEDLINE
| ID: mdl-36689364
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pancreatite
/
Epóxido Hidrolases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article