Title: From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis.
Authors: Codony, Sandra; Calvó-Tusell, Carla; Valverde, Elena; Osuna, Sílvia; Morisseau, Christophe; Loza, M Isabel; Brea, José; Pérez, Concepción; Rodríguez-Franco, María Isabel; Pizarro-Delgado, Javier; Corpas, Rubén; Griñán-Ferré, Christian; Pallàs, Mercè; Sanfeliu, Coral; Vázquez-Carrera, Manuel; Hammock, Bruce D; Feixas, Ferran; Vázquez, Santiago
Published In J Med Chem, (2021 05 13)
Abstract: 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.
PubMed ID: 33945278
MeSH Terms: Acute Disease; Adamantane/chemistry*; Adamantane/metabolism; Adamantane/pharmacology; Adamantane/therapeutic use; Animals; Binding Sites; Catalytic Domain; Cell Membrane Permeability/drug effects; Drug Design*; Drug Stability; Enzyme Inhibitors/chemistry*; Enzyme Inhibitors/metabolism; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/therapeutic use; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Half-Life; Humans; Hydrophobic and Hydrophilic Interactions; Male; Mice; Mice, Inbred C57BL; Molecular Dynamics Simulation; Pancreatitis/drug therapy; Rats; Structure-Activity Relationship