2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity.

Juan Martín-López,Santiago Vázquez,Clara Bartra,Christophe Morisseau,Bruce D Hammock,José Brea,Sandra Codony,Coral Sanfeliu,María Isabel Loza

doi:10.3390/ph14121323

Abstract

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU.

Highlights

Soluble epoxide hydrolase metabolizes epoxyeicosatrienoic acids (EETs), potent endogenous anti-inflammatory mediators [1,2,3], into the corresponding dihydroxyeicosatrienoic acids, which are much less biologically active [4,5]
Taking into account that several adamantane-based and benzene-based ureas are endowed with very potent activity as sEH inhibitors (sEHI) [14,15,16,17], that both AR9281 and EC5026 feature an acylpiperidine unit, and that the highly hydrophobic pocket of soluble epoxide hydrolase (sEH) seems able
On the other hand, inspired by the structure of amide AS2586114, a very potent sEHI developed by Astellas [24,25], we explored the series of N-aryl derivatives 10a–e (Scheme 2)

Summary

Introduction

Soluble epoxide hydrolase (sEH, EPHX2, EC 3.3.2.3) metabolizes epoxyeicosatrienoic acids (EETs), potent endogenous anti-inflammatory mediators [1,2,3], into the corresponding dihydroxyeicosatrienoic acids, which are much less biologically active [4,5]. Pharmaceuticals 2021, 14, 1323 to accommodate very large hydrophobic groups [18], we have recently designed, synthesized and pharmacologically evaluated a novel series of ureas featuring the benzohomoadamantane scaffold as hydrophobic moiety, that merges in its polycyclic structure an adamantane-related core with an aromatic ring [19]. Several of these novel sEHI-based ureas were low nanomolar inhibitors of the human and murine sEH, but most of them, as 1, showed high melting points, limited solubility, and unacceptably low microsomal stabilities (Figure 2) [19]. Taking into account that amides are good pharmacophores for sEHI [20], the aim of the present study was to replace the urea moiety of 1 by an amide group in order to improve the physical properties and, its very poor microsomal stability to improve availability and in vivo efficacy

Objectives

Methods

Results

Conclusion