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

Abstract

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.

• Authors: Sandra Codony, Eugènia Pujol, Javier Pizarro, Ferran Feixas, Elena Valverde, M Isabel Loza, José M Brea, Elena Saez, Julen Oyarzabal, Antonio Pineda-Lucena, Belén Pérez, Concepción Pérez, María Isabel Rodríguez-Franco, Rosana Leiva, Sílvia Osuna, Christophe Morisseau, Bruce D Hammock, Manuel Vázquez-Carrera, Santiago Vázquez
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 17 Pg. 9237-9257 (09 10 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 32787085 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Urea
• Epoxide Hydrolases

Topics

• Acute Disease
• Animals
• Binding Sites
• Catalytic Domain
• Cell Line
• Cell Survival (drug effects)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (drug effects)
• Enzyme Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Epoxide Hydrolases (antagonists & inhibitors, metabolism)
• Half-Life
• Humans
• Mice
• Microsomes (metabolism)
• Molecular Dynamics Simulation
• Pancreatitis (chemically induced, drug therapy, pathology)
• Rats
• Solubility
• Structure-Activity Relationship
• Urea (chemistry, metabolism, pharmacology, therapeutic use)