Musella_2023_J.Med.Chem__

Reference

Title : Design, Synthesis, and Pharmacological Characterization of a Potent Soluble Epoxide Hydrolase Inhibitor for the Treatment of Acute Pancreatitis - Musella_2023_J.Med.Chem__
Author(s) : Musella S , D'Avino D , Peltner LK , Di Sarno V , Cerqua I , Merciai F , Vestuto V , Ciaglia T , Smaldone G , Di Matteo F , Di Micco S , Napolitano V , Bifulco G , Pepe G , Sommella EM , Basilicata MG , Aquino G , Gomez-Monterrey IM , Campiglia P , Ostacolo C , Roviezzo F , Werz O , Rossi A , Bertamino A
Ref : Journal of Medicinal Chemistry , : , 2023
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.

PubMedSearch : Musella_2023_J.Med.Chem__
PubMedID: 37334504
Gene_locus related to this paper: human-EPHX2

Related information

Inhibitor Adamantyl-urea-Cpd28
Gene_locus human-EPHX2

Citations formats

Musella S, D'Avino D, Peltner LK, Di Sarno V, Cerqua I, Merciai F, Vestuto V, Ciaglia T, Smaldone G, Di Matteo F, Di Micco S, Napolitano V, Bifulco G, Pepe G, Sommella EM, Basilicata MG, Aquino G, Gomez-Monterrey IM, Campiglia P, Ostacolo C, Roviezzo F, Werz O, Rossi A, Bertamino A (2023)
Design, Synthesis, and Pharmacological Characterization of a Potent Soluble Epoxide Hydrolase Inhibitor for the Treatment of Acute Pancreatitis
Journal of Medicinal Chemistry :

Musella S, D'Avino D, Peltner LK, Di Sarno V, Cerqua I, Merciai F, Vestuto V, Ciaglia T, Smaldone G, Di Matteo F, Di Micco S, Napolitano V, Bifulco G, Pepe G, Sommella EM, Basilicata MG, Aquino G, Gomez-Monterrey IM, Campiglia P, Ostacolo C, Roviezzo F, Werz O, Rossi A, Bertamino A (2023)
Journal of Medicinal Chemistry :