Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

Veronika Temml,Daniela Schuster,Gregor Schubert,Zsofia Kutil,Birgit Waltenberger,Hermann Stuppner,Erik Romp,Ulrike Garscha,Oliver Werz,Barbara Matuszczak,Jana Gerstmeier

doi:10.1038/srep42751

Abstract

Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

Highlights

IntroductionThe “one-drug-hits-one-target” approach has essentially lost ground
In recent years, the “one-drug-hits-one-target” approach has essentially lost ground
We first focused on the development and validation of ligand-based pharmacophore models for FLAP based on published FLAP inhibitors

Summary

Introduction

The “one-drug-hits-one-target” approach has essentially lost ground. Several successfully marketed drugs were shown to affect a multiplicity of targets in retrospective. The rational development of chemical structures that contain fragments to inhibit multiple targets, so-called designed multiple ligands (DML), has emerged as a highly interesting field of research with promise for better pharmacotherapies[3]. By combining multiple pharmacophore models for different targets in a virtual screening, it is possible to discover structures that contain fragments to affect two or more targets[6]. A key biochemical pathway for targeting multiple inflammatory conditions is the arachidonic acid (AA) cascade. FLAP has regained attention as a drug target, most prominently with GSK2190915, a novel promising indole-based derivative that completed phase II trials for the treatment of asthma[15]. In 2015 research on FLAP inhibitors received another boost with the development of a series of oxadiaozole-containing FLAP inhibitors, shown by Takahashi et al.[16] and the discovery of AZD6642, another potent FLAP inhibitor[17]

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