Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases.
Yuanguang ChenLu ChenHuashen XuRuolin CaoChristophe MorisseauMaoying ZhangYajie ShiBruce D HammockJieru WangJunning ZhuangZhongbo LiuGuoliang ChenPublished in: Journal of medicinal chemistry (2023)
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.
Keyphrases
- lps induced
- anti inflammatory
- cell adhesion
- inflammatory response
- rheumatoid arthritis
- oxidative stress
- high glucose
- acute kidney injury
- intensive care unit
- drug induced
- diabetic rats
- nitric oxide
- high throughput
- poor prognosis
- small molecule
- type diabetes
- binding protein
- septic shock
- toll like receptor
- south africa
- endothelial cells
- immune response
- adverse drug
- nitric oxide synthase
- mass spectrometry
- neuropathic pain
- adipose tissue
- combination therapy
- skeletal muscle
- protein protein
- free survival