RT Journal Article
T1 From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis
A1 Codony, Sandra
A1 Calvó-Tusell, Carla
A1 Valverde, Elena
A1 Osuna, Sílvia
A1 Morisseau, Christophe
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Pérez, Concepción
A1 Rodríguez-Franco, María Isabel
A1 Pizarro-Delgado, Javier
A1 Corpas, Rubén
A1 Griñán-Ferré, Christian
A1 Pallàs, Mercè
A1 Sanfeliu, Coral
A1 Vázquez-Carrera, Manuel
A1 Hammock, Bruce D.
A1 Feixas, Ferran
A1 Vázquez, Santiago
K1 Inhibition
K1 Inhibitors
K1 Peptides and proteins
K1 Scaffolds
K1 Urea
AB The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.
PB ACS Publications
SN 0022-2623
YR 2021
FD 2021-05-04
LK https://hdl.handle.net/10347/45429
UL https://hdl.handle.net/10347/45429
LA eng
NO J. Med. Chem. 2021, 64, 9, 5429–5446
DS Minerva
RD 24 abr 2026