Recent advances for FLAP inhibitors

Pettersen, Daniel; Davidsson, Öjvind; Whatling, Carl

doi:10.1016/j.bmcl.2015.04.090

Cited by 38 publications

(42 citation statements)

References 32 publications

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“…Clinically relevant LT-modifying agents include inhibitors of FLAP or 5-LO, which are currently under clinical investigation as candidates for the treatment of respiratory and cardiovascular diseases (18,19). Despite intensive research, only the direct 5-LO inhibitor zileuton entered the market as an antiasthmatic drug, while other compounds failed in clinical trials due to lack of efficacy Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP).…”

Section: Introductionmentioning

confidence: 99%

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Pace¹,

Pergola²,

Dehm³

et al. 2017

Journal of Clinical Investigation

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Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development

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Section: Introductionmentioning

confidence: 99%

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Pace¹,

Pergola²,

Dehm³

et al. 2017

Journal of Clinical Investigation

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“…Here, we disclose diflapolin as a potent, dual inhibitor of FLAP and sEH with marked anti-inflammatory efficacy in vivo and high target selectivity. Side-by-side studies of diflapolin with the “FLAP benchmark inhibitor” MK886 40 revealed comparable potencies for inhibition of 5-LOX product biosynthesis in human leukocytes in vitro , and about equal effectiveness in suppression of LT formation and inflammatory properties in vivo using murine zymosan-induced peritonitis models.…”

Section: Discussionmentioning

confidence: 99%

“…homogenates) 41 . Nevertheless, FLAP is essential for LT biosynthesis in intact cells and in vivo , as reflected by results from various pharmacological approaches 40 and from gene intervention using FLAP knock-out mice 42 . Experimental evidence suggests that FLAP operates as a 5-LOX helper protein for transforming AA to 5-HPETE and for dehydration of 5-HPETE to LTA 4 29 , 43 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase

Garscha

Romp

Rossi

et al. 2017

Sci Rep

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Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N′-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH. Diflapolin inhibited 5-LOX product formation in intact human monocytes and neutrophils with IC50 = 30 and 170 nM, respectively, and suppressed the activity of isolated sEH (IC50 = 20 nM). Characteristic for FLAP inhibitors, diflapolin (I) failed to inhibit isolated 5-LOX, (II) blocked 5-LOX product formation in HEK cells only when 5-LOX/FLAP was co-expressed, (III) lost potency in intact cells when exogenous AA was supplied, and (IV) prevented 5-LOX/FLAP complex assembly in leukocytes. Diflapolin showed target specificity, as other enzymes related to AA metabolism (i.e., COX1/2, 12/15-LOX, LTA4H, LTC4S, mPGES1, and cPLA2) were not inhibited. In the zymosan-induced mouse peritonitis model, diflapolin impaired vascular permeability, inhibited cysteinyl-LTs and LTB4 formation, and suppressed neutrophil infiltration. Diflapolin is a highly active dual FLAP/sEH inhibitor in vitro and in vivo with target specificity to treat inflammation-related diseases.

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“…The 5-LOX inhibitor zileuton has been used successfully for the control of asthma. Currently, 5-LOX inhibitors are being developed by pharmaceutical companies (36). These inhibitors prevent the transportation of 5-LOX from the nucleus to the cytoplasm, leading to the suppression of 5-hydroperoxyeicosatetraenoic acid production.…”

Section: Discussionmentioning

confidence: 99%

Benzoxazole derivatives suppress lipopolysaccharide-induced mast cell activation

et al. 2018

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Mast cells are central regulators of allergic inflammation that function by releasing various proallergic inflammatory mediators, including histamine, eicosanoids and proinflammatory cytokines. Occasionally, bacterial infections may initiate or worsen allergic inflammation. A number of studies have indicated that activation of lipoxygenase in mast cells positive regulates allergic inflammatory responses by generating leukotrienes and proinflammatory cytokines. In the present study, the effects of benzoxazole derivatives on the lipopolysaccharide (LPS)‑induced expression of proinflammatory cytokines, production of histamine and surface expression of co‑stimulatory molecules on bone marrow-derived mast cells (BMMCs) were studied. The benzoxazole derivatives significantly reduced the expression of interleukin (IL)‑1β, IL‑6, IL‑13, tumor necrosis factor‑α, perilipin (PLIN) 2, and PLIN3 in BMMCs treated with LPS. Furthermore, histamine production was suppressed in BMMCs treated with LPS, or treated with phorbol-12-myristate-13-acetate/ionomycin. Benzoxazole derivatives marginally affected the surface expression of cluster of differentiation (CD)80 and CD86 on BMMCs in the presence of LPS, although LPS alone did not increase the expression of those proteins. Therefore, benzoxazole derivatives inhibited the secretion of proinflammatory cytokines in mast cells and may be potential candidate anti‑allergic agents to suppress mast cell activation.

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Recent advances for FLAP inhibitors

Cited by 38 publications

References 32 publications

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase

Benzoxazole derivatives suppress lipopolysaccharide-induced mast cell activation

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