Addition of a 5-lipoxygenase-activating protein inhibitor to an inhaled corticosteroid (ICS) or an ICS/long-acting beta-2-agonist combination in subjects with asthma

Snowise, Neil G; Clements, Diane; Ho, Shuyen; Follows, Richard

doi:10.1185/03007995.2013.842163

Cited by 12 publications

(8 citation statements)

References 20 publications

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“…In the first study, active treatment (300 mg dosage) significantly influenced the mean peak expiratory flow (p = 0.049), symptom-free days (p = 0.035) and percentage of symptom-free 24 h periods (p = 0.030). Similar significant therapeutic benefits on daytime and nighttime and on symptom-free days were also reported in the second study [31].…”

Section: Flap Inhibitorssupporting

confidence: 73%

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

Antoniu

2014

Expert Opinion on Therapeutic Targets

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Section: Flap Inhibitorssupporting

confidence: 73%

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

Antoniu

2014

Expert Opinion on Therapeutic Targets

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“…BAY X-1005/DG-031) or hybrids thereof (MK591), have been developed and evaluated in clinical trials, but these compounds were not further explored (Evans et al, 2008;Sampson, 2009;Ferguson, 2012). Recent re-assessment of FLAP inhibitors of the indole series provided GSK2190915 as a promising candidate that is currently undergoing phase II trials in patients with asthma (Stock et al, 2011;Bain et al, 2013;Follows et al, 2013;Kent et al, 2013;Snowise et al, 2013). Also, the anti-inflammatory compound licofelone, which was originally developed as a dual inhibitor of the COX and 5-LOX pathways (Laufer et al, 1994a,b), targets FLAP (Fischer et al, 2007) and has reached clinical phase III for osteoarthritis (Raynauld et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The novel benzimidazole derivative BRP‐7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5‐lipoxygenase‐activating protein (FLAP)

Pergola

Gerstmeier

Mönch

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSELeukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis. EXPERIMENTAL APPROACHWe analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis. KEY RESULTSBRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. CONCLUSIONS AND IMPLICATIONSBRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development. Abbreviations12-HHT, 12-hydroxy-5,8,10-heptadecatrienoic acid; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-LOX, 5-lipoxygenase; AA, arachidonic acid; cPLA2, cytosolic PLA2; cysLTs, cysteinyl LTs; DPPH, 1,1-diphenyl-2-picrylhydrazyl; FLAP, fMLP,; hERG, human ether-a-go-go gene; HWB, human whole blood; IFM, immunofluorescence microscopy; mPGES-1, microsomal PGE2 synthase-1; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; PGC buffer, PBS pH 7.4 containing 1 mg·mL

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“…Only comparatively few chemical scaffolds have been reported as FLAP inhibitors such as MK-886, an indole-class compound 13 , and a series of quinolone-based inhibitors 14 , but in both cases research was discontinued. Recently however, 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 .…”

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confidence: 99%

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

Temml

Garscha²,

Romp³

et al. 2017

Sci Rep

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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.

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Addition of a 5-lipoxygenase-activating protein inhibitor to an inhaled corticosteroid (ICS) or an ICS/long-acting beta-2-agonist combination in subjects with asthma

Abstract: Clinicaltrials.gov identifiers: NCT01156792 and NCT01248975.

Cited by 12 publications

References 20 publications

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

The novel benzimidazole derivative BRP‐7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5‐lipoxygenase‐activating protein (FLAP)

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

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