TY - JOUR
T1 - 2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors
T2 - In Vivo Evaluation in a Murine Model of Acute Pancreatitis
AU - Codony, Sandra
AU - Pujol, Eugènia
AU - Pizarro, Javier
AU - Feixas, Ferran
AU - Valverde, Elena
AU - Loza, M. Isabel
AU - Brea, José M.
AU - Saez, Elena
AU - Oyarzabal, Julen
AU - Pineda-Lucena, Antonio
AU - Pérez, Belén
AU - Pérez, Concepción
AU - Rodríguez-Franco, María Isabel
AU - Leiva, Rosana
AU - Osuna, Sílvia
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Vázquez-Carrera, Manuel
AU - Vázquez, Santiago
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85090870611&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c00310
DO - 10.1021/acs.jmedchem.0c00310
M3 - Article
C2 - 32787085
AN - SCOPUS:85090870611
VL - 63
SP - 9237
EP - 9257
IS - 17
ER -