FLAP/5-lipoxygenase-activating protein (IC50 = 1.6 nM)[1]
Quiflapon is accessible in whole blood from humans, squirrel monkeys, and rats (IC50 values 510, 69, and 9 nM, respectively), as well as in intact human and induced rat polymorphonuclear leukocytes (PMNL) (IC50 values 3.1 and 6.1 nM, respectively). Rat 5-lipoxygenase is not affected by quilapon. Quiflapon is photoaffinity-tagged to inhibit 5-lipoxygenase-activating protein (FLAP) using two distinct photoaffinity ligands. It exhibits a high affinity for FLAP, with an IC50 value of 1.6 nM in the FLAP binding assay. In human PMNL, 5-lipoxygenase translocation from the cytosol to the membrane can be blocked to prevent 5-lipoxygenase from activating [1].
Quiflapon (MK591, MK-0591) is a 5-lipoxygenase-activating protein (FLAP) inhibitor. It inhibits leukotriene (LT) production. [2]

Quiflapon is accessible in whole blood from humans, squirrel monkeys, and rats (IC50 values 510, 69, and 9 nM, respectively), as well as in intact human and induced rat polymorphonuclear leukocytes (PMNL) (IC50 values 3.1 and 6.1 nM, respectively). Rat 5-lipoxygenase is not affected by quilapon. Quiflapon is photoaffinity-tagged to inhibit 5-lipoxygenase-activating protein (FLAP) using two distinct photoaffinity ligands. It exhibits a high affinity for FLAP, with an IC50 value of 1.6 nM in the FLAP binding assay. In human PMNL, 5-lipoxygenase translocation from the cytosol to the membrane can be blocked to prevent 5-lipoxygenase from activating [1].

Quiflapon has been shown to be a strong inhibitor of LT biosynthesis in vivo in three different settings: an ex vivo challenge in blood drawn from treated rats and squirrel monkeys, a rat pleurisy model, and the inhibition of LTE4 excretion in the urine. Test for allergens in sheep with allergies. Quiflapon was found to have an inhibitory effect on antigen-induced bronchoconstriction (both early and late responses) in ascaris-challenged sheep, ascaris-challenged squirrel monkeys, and inbred rats pretreated with methierg [1]. For days 1-4, 5-9, or 10-14, puppies received daily subcutaneous injections of vehicle or Quiflapon at 10, 20, or 40 mg/kg. Lungs were inflated, fixed, and stained for morphometric and histological studies on day 14. Both the untreated hyperoxia group and the Quiflapon-treated hyperoxia group demonstrated distinct signs of aberrant alveolarization without any inflammation [2].

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In newborn mice exposed to 85% oxygen (hyperoxia) for 14 days, subcutaneous administration of MK-0591 prevented aberrant alveolarization in a dose- and time-dependent manner.
Hyperoxia-exposed mice treated with 40 mg/kg MK-0591 during postnatal days 1-4 (P1-P4) showed lung histomorphology and morphometric parameters (number of air spaces, mean perimeter, mean area, perimeter/area ratio) comparable to room air controls.
Hyperoxia-exposed mice treated with 20 or 40 mg/kg MK-0591 during postnatal days 10-14 (P10-P14) also showed lung histomorphology and morphometric parameters similar to room air controls.
No protective effect was observed when MK-0591 (10, 20, or 40 mg/kg) was administered during postnatal days 5-9 (P5-P9); the alveolarization remained aberrant and comparable to hyperoxia controls (vehicle-treated). [2]

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In newborn mice exposed to 85% oxygen (hyperoxia) for 14 days, subcutaneous administration of MK-0591 prevented aberrant alveolarization in a dose- and time-dependent manner.
Hyperoxia-exposed mice treated with 40 mg/kg MK-0591 during postnatal days 1-4 (P1-P4) showed lung histomorphology and morphometric parameters (number of air spaces, mean perimeter, mean area, perimeter/area ratio) comparable to room air controls.
Hyperoxia-exposed mice treated with 20 or 40 mg/kg MK-0591 during postnatal days 10-14 (P10-P14) also showed lung histomorphology and morphometric parameters similar to room air controls.
No protective effect was observed when MK-0591 (10, 20, or 40 mg/kg) was administered during postnatal days 5-9 (P5-P9); the alveolarization remained aberrant and comparable to hyperoxia controls (vehicle-treated). [2]

For each experiment, equal numbers of cells were plated in six-well plates; 24 h later media were removed and fresh media containing either MK-591 (1 μM, 10 μM or 25 μM) or vehicle were added. After incubation for 24 h, supernatants were collected for Aβ and LDH measurement, and cell pellets harvested in lytic buffer for immunoblot analyses as described in the previous paragraphs.
For transfection studies, N2A-APPswe cells were transfected with 1 μg Myc-tagged mΔE-Notch-1 complementary DNA overnight by using Lipofectamine 2000 (Invitrogen). The media were removed and fresh media containing MK-591, L685,458 or vehicle were added. After incubation for 24 h, cells lysates were collected NICD expression levels assayed by western blot analysis.[3]

MK-0591 was a potent inhibitor of LT biosynthesis in vivo, first, following ex vivo challenge of blood obtained from treated rats and squirrel monkeys, second, in a rat pleurisy model, and, third, as monitored by inhibition of the urinary excretion of LTE4 in antigen-challenged allergic sheep. Inhibition of antigen-induced bronchoconstriction by MK-0591 was observed in inbred rats pretreated with methysergide, Ascaris-challenged squirrel monkeys, and Ascaris-challenged sheep (early and late phase response).[1]

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Newborn mice were exposed to either room air or hyperoxia for 14 days. Pups were treated with either vehicle or MK-0591 10, 20, or 40 mg/kg subcutaneously daily for days 1-4, 5-9, or 10-14. On day 14, the lungs were inflated, fixed, and stained for histopathological and morphometric analyses. Hyperoxia groups treated with MK-0591 20 or 40 mg/kg during days P1-P4 or P10-P14 showed alveolarization that resembled that of room air controls while untreated hyperoxia groups showed definite evidence of aberrant alveolarization but no inflammation. In a hyperoxia-exposed newborn mice model, a FLAP inhibitor given during critical window periods may prevent aberration of alveolarization in a dose- and time-dependent manner.[2]

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MK-0591 in powder form was reconstituted in a vehicle consisting of H₂O and Tween 80 in a 4:1 ratio to a final concentration of 8 mg/mL.
Newborn FVB/n mice were exposed to either room air or 85% oxygen from birth until postnatal day 14.
Pups received daily subcutaneous injections of either vehicle or MK-0591 at doses of 10, 20, or 40 mg/kg. Treatment windows were either postnatal days 1-4 (P1-P4), 5-9 (P5-P9), or 10-14 (P10-P14).
Oxygen exposure was conducted in Plexiglas chambers maintained at 85% oxygen, 26°C, and 70% humidity, with continuous oxygen flow and CO₂ absorption. Nursing dams were rotated every 24 hours between hyperoxia and room air litters.
On postnatal day 14, mice were euthanized with an intraperitoneal overdose of pentobarbital sodium. Lungs were inflation-fixed with paraformaldehyde at 25 cm H₂O pressure, then processed for paraffin embedding, sectioning, and hematoxylin & eosin staining for histopathological and morphometric analysis. [2]

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MK-0591 in powder form was reconstituted in a vehicle consisting of H₂O and Tween 80 in a 4:1 ratio to a final concentration of 8 mg/mL.
Newborn FVB/n mice were exposed to either room air or 85% oxygen from birth until postnatal day 14.
Pups received daily subcutaneous injections of either vehicle or MK-0591 at doses of 10, 20, or 40 mg/kg. Treatment windows were either postnatal days 1-4 (P1-P4), 5-9 (P5-P9), or 10-14 (P10-P14).
Oxygen exposure was conducted in Plexiglas chambers maintained at 85% oxygen, 26°C, and 70% humidity, with continuous oxygen flow and CO₂ absorption. Nursing dams were rotated every 24 hours between hyperoxia and room air litters.
On postnatal day 14, mice were euthanized with an intraperitoneal overdose of pentobarbital sodium. Lungs were inflation-fixed with paraformaldehyde at 25 cm H₂O pressure, then processed for paraffin embedding, sectioning, and hematoxylin & eosin staining for histopathological and morphometric analysis. [2]

[1]. Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)- indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1992 Jun;70(6):799-8.

[2]. 5-Lipoxygenase-activating protein (FLAP) inhibitor MK-0591 prevents aberrant alveolarization in newborn mice exposed to 85% oxygen in a dose- and time-dependent manner. Lung. 2011 Feb;189(1):43-50.

MK-0591 (3-[1-(4-chlorobenzyl)-3-(tert-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethylpropionic acid, formerly known as L-686,708) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMNLs) and induced rat polymorphonuclear leukocytes (PMNLs) (IC50 values of 3.1 nM and 6.1 nM, respectively). It also exhibits inhibitory activity in whole blood from humans, squirrel monkeys, and rats (IC50 values of 510 nM, 69 nM, and 9 nM, respectively). MK-0591 has no effect on rat 5-lipoxygenase. MK-0591 exhibits a high affinity for 5-lipoxygenase-activated protein (FLAP), with an IC50 value of 1.6 nM in the FLAP binding assay, and this is confirmed by its ability to inhibit photoaffinity labeling of FLAP by two different photoaffinity ligands. In human polymorphonuclear leukocytes (PMNL), the inhibitory effect of MK-0591 on 5-lipoxygenase activation was demonstrated by inhibiting the translocation of 5-lipoxygenase from the cytosol to the cell membrane. MK-0591 is a potent in vivo inhibitor of leukotriene (LT) biosynthesis, as demonstrated firstly by in vitro stimulation of the blood of rats and squirrel monkeys treated with MK-0591; secondly, by a rat pleurisy model; and thirdly, by inhibiting the excretion of LTE4 in the urine of antigen-induced allergic sheep. The inhibitory effect of MK-0591 on antigen-induced bronchoconstriction was observed in inbred rats pretreated with lysergic acid diethylamine, squirrel monkeys infected with Ascaris lumbricoides, and sheep infected with Ascaris lumbricoides (early and late responses). These results indicate that MK-0591 is a potent inhibitor of leukotriene biosynthesis in vitro and in vivo, suggesting that the compound is suitable for assessing the role of leukotrienes in pathological conditions. [1]

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Bronchopulmonary dysplasia is characterized by long-term oxygen dependence due to impaired gas exchange capacity. This is mainly attributed to alveolar hypoplasia and abnormalities caused by damage such as hyperoxia. Leukotrienes are associated with hyperoxia-induced alveolar development inhibition. We hypothesized that administration of a 5-lipoxygenase-activating protein (FLAP) inhibitor to newborn mice exposed to 85% oxygen could prevent abnormal alveolarization in a dose- and time-dependent manner. Newborn mice were exposed to normal air or hyperoxia for 14 days, respectively. Young mice received subcutaneous injections of either the excipient or MK-0591 (10, 20, or 40 mg/kg) once daily for 1–4, 5–9, or 10–14 days, respectively. On day 14, lung tissue was inflated, fixed, and stained for histopathological and morphometric analysis. Mice in the hyperoxia group treated with MK-0591 (20 or 40 mg/kg) on days P1–P4 or P10–P14 showed alveolarization similar to the normal air control group, while untreated hyperoxia mice exhibited markedly abnormal alveolarization without inflammatory response. In a neonatal mouse model exposed to hyperoxia, administration of FLAP inhibitors during the critical window period dose- and time-dependently prevented abnormal alveolar development. [2]

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This study used a neonatal mouse model exposed to 85% oxygen, which induced alveolar developmental abnormalities (reduced number of air spaces, enlarged air spaces, and reduced septa) without significant inflammation or tissue necrosis, mimicking some features of “newborn” bronchopulmonary dysplasia (BPD).
The protective effect of the FLAP inhibitor MK-0591 suggests that the leukotriene pathway is involved in hyperoxia-driven alveolar developmental abnormalities, and its mechanism may not be limited to simple anti-inflammatory effects.
The efficacy of MK-0591 depends mainly on the timing of administration, being effective in the late cystic/early alveolar phase (P1-P4) and late alveolar phase (P10-P14), but ineffective in the early alveolar phase (P5-P9), indicating a specific susceptibility window and the potential to reverse alveolar developmental defects. [2]

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This study used a model of newborn mice exposed to 85% oxygen, which induced abnormal alveolar development (reduced number of air spaces, enlarged air spaces, and reduced septa), but without obvious inflammation or tissue necrosis, mimicking some features of “newborn” bronchopulmonary dysplasia (BPD). The protective effect of the FLAP inhibitor MK-0591 suggests that the leukotriene pathway is involved in hyperoxia-driven abnormal alveolar formation, and its mechanism of action may go beyond simple anti-inflammatory effects. The efficacy of MK-0591 is closely related to the time of administration, being effective in the late cystic/early alveolar stage (P1-P4) and late alveolar stage (P10-P14), but ineffective in the early alveolar stage (P5-P9), indicating the existence of a specific susceptible window period, and that alveolar formation defects may be reversed during this window period. [2]

C34H35CLN2O3S

587.17100

586.205

C, 69.55; H, 6.01; Cl, 6.04; N, 4.77; O, 8.17; S, 5.46

136668-42-3

Quiflapon sodium;147030-01-1

60923

White to off-white solid powder

1.2±0.1 g/cm3

751.3±60.0 °C at 760 mmHg

408.2±32.9 °C

0.0±2.6 mmHg at 25°C

1.617

8.31

1

5

10

41

873

0

O=C(O)C(C)(C)CC1=C(SC(C)(C)C)C2=C(C=CC(OCC3=NC4=CC=CC=C4C=C3)=C2)N1CC5=CC=C(Cl)C=C5

NZOONKHCNQFYCI-UHFFFAOYSA-N

InChI=1S/C34H35ClN2O3S/c1-33(2,3)41-31-27-18-26(40-21-25-15-12-23-8-6-7-9-28(23)36-25)16-17-29(27)37(20-22-10-13-24(35)14-11-22)30(31)19-34(4,5)32(38)39/h6-18H,19-21H2,1-5H3,(H,38,39)

3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoic acid

Quiflapon free acid; MK 591; MK-591; MK591; L 686708; L-686708; L686708; L-686,708; L 686,708; Quiflapon; 136668-42-3; MK-0591; Quiflapon [INN]; Quiflapon free acid; 3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoic acid; MK 591; CHEMBL16596; L686,708;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~85.15 mM)

Solubility in Formulation 1: 2.5 mg/mL (4.26 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)