From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis.

Sandra Codony,Bruce D Hammock,Concepción Pérez,Manuel Vázquez-Carrera,M Isabel Loza,José Brea,Carla Calvó-Tusell,Christophe Morisseau,Ferran Feixas,Santiago Vázquez,Mercè Pallàs,Javier Pizarro-Delgado,Coral Sanfeliu,María Isabel Rodríguez-Franco,Rubén Corpas,Elena Valverde,Sílvia Osuna,Christian Griñán-Ferré

doi:10.1021/acs.jmedchem.0c01601

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.

Highlights

In mammals, arachidonic acid, a polyunsaturated fatty acid, is metabolized by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs)
The EETs are rapidly metabolized by the soluble epoxide hydrolase into the corresponding dihydroxyeicosatrienoic acids, which are less biologically active.[3,4]
Using urea-based sEH inhibitors (sEHIs) with lipophilic units of very different sizes, we recently found that the pocket of the soluble epoxide hydrolase (sEH) can accommodate polycycles of a quite diverse volume and that the replacement of the adamantane moiety by larger polycyclic rings, such as the diamantane moiety, may be better than the replacement by smaller ones

Summary

Introduction

Arachidonic acid, a polyunsaturated fatty acid, is metabolized by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). X-ray crystallographic studies revealed that sEH has an Lshaped active pocket with the catalytic residues situated at the corner. Each side of the pocket (10 and 15 Å long) accepts a variety of functional groups, the entire pocket is essentially hydrophobic.[7] a number of very potent sEH inhibitors (sEHIs) feature lipophilic moieties such as adamantyl or phenyl groups (Figure 1), limiting their usefulness.[5,6]

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Results

Conclusion