2‑Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis

• Published in: Journal of medicinal chemistry 2020-09, Vol.63 (17), p.9237-9257
• Main Authors: Codony, Sandra, Pujol, Eugènia, Pizarro, Javier, Feixas, Ferran, Valverde, Elena, Loza, M. Isabel, Brea, José M, Saez, Elena, Oyarzabal, Julen, Pineda-Lucena, Antonio, Pérez, Belén, Pérez, Concepción, Rodríguez-Franco, María Isabel, Leiva, Rosana, Osuna, Sílvia, Morisseau, Christophe, Hammock, Bruce D, Vázquez-Carrera, Manuel, Vázquez, Santiago
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Binding Sites; Catalytic Domain; Cell Line; Cell Survival - drug effects; Disease Models, Animal; Endoplasmic Reticulum Stress - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Half-Life; Humans; Mice; Microsomes - metabolism; Molecular Dynamics Simulation; Pancreatitis - chemically induced; Pancreatitis - drug therapy; Pancreatitis - pathology; Rats; Solubility; Structure-Activity Relationship; Urea - chemistry; Urea - metabolism; Urea - pharmacology; Urea - therapeutic use
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00310

In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.