Design, Synthesis, and Pharmacological Characterization of a Potent Soluble Epoxide Hydrolase Inhibitor for the Treatment of Acute Pancreatitis.
J Med Chem
; 66(13): 9201-9222, 2023 07 13.
Article
em En
| MEDLINE
| ID: mdl-37334504
ABSTRACT
Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for the treatment of AP. Synthesized compounds were screened in vitro for their sEH inhibitory potency and selectivity, and the results were rationalized by means of molecular modeling studies. The most potent compounds were studied in vitro for their pharmacokinetic profile, where compound 28 emerged as a promising lead. In fact, compound 28 demonstrated a remarkable in vivo efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity in vivo. Finally, pharmacokinetic assessment demonstrated a suitable profile of 28 in vivo. Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pancreatite
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Itália