LTE₄ ( Ki = 0.63 nM ); LTD₄ ( Ki = 0.99 nM ); LTC₄ ( Ki = 5640 nM )

Pranlukast reduces NF-kappa B activation in 1.3% DMSO-differentiated Jurkat and U-937 cells by approximately 30% and 40%, respectively. In 1.3% DMSO-differentiated U-937 and Jurkat cells, pranlukast and MK-571 inhibit NF-kappa B activation in a dose-related fashion. The production of IL-6 in PBMC stimulated by LPS is inhibited by pranlukast and MK-571 by approximately 65% and 15%, respectively. (Source: ) 10 mM LTD4-evoked 35SO4 output is significantly inhibited by both zafirlukast and pranlukast in a concentration-dependent manner; the maximal inhibitions are 83% and 78% at 10 mM zafirlukast and 0.3 mM and 0.6 mM, respectively, for both drugs. Pranlukast (0.5 microM) causes a parallel rightward shift in the LTD4 concentration-response curve with a pKB.[3] The ovalbumin-induced secretion in the tracheae of sensitized guinea pigs is markedly suppressed by either pranlukast (5 microM) or zafirlukast (65%), respectively. In [2] Pranlukast also inhibits NF-kappaB activation induced by phorbol 12-myristate 13-acetate (PMA). Pranlukast also significantly inhibits LPS-induced MUC2 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) analysis in NCI-H292 cells. Pranlukast also inhibits LPS-induced MUC2 gene expression in HM3-MUC2 cells.[3]

Pranlukast increases neuron densities in the cortex and hippocampal CA1 region in the mice's ischemic hemispheres and dramatically decreases the volume of lesion. Pranlukast also significantly lessens the scar wall's thickness in mice's ischemic hemispheres.[4]

Pranlukast is a leukotriene 1 (LT1) receptor antagonist and is effective against bronchial asthma. Pranlukast inhibits contraction of the tracheal muscle, and thereby antagonizes the binding of LTC4, LTD4 and LTE4. However, the action of pranlukast on monocytes/macrophages and T cells is unknown. Objective: We examined whether or not pranlukast inhibits TNF-alpha-induced activation of nuclear transcription factor NF-kappa B, a factor that is essential for the expression of proinflammatory cytokines, on human monocytic 1.3% dimethylsulphoxide (DMSO)-differentiated U-937 cells, which have cysteinyl LT1 (CysLT1) receptors on their membranes, and T cells (Jurkat), which do not. Methods: We examined whether or not LTC4, LTD4 or LTE4 induced NF-kappa B activation in 1.3% DMSO-differentiated U-937 cells by Western blotting. The inhibitory effects of pranlukast and MK-571, which is an LTD4 receptor-selective antagonist, on TNF-alpha-induced NF-kappa B activation was evaluated by Western blotting and flow cytometry, and those on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production in peripheral blood mononuclear cells (PBMC) were evaluated by enzyme-linked immunosorbent assaying. Results: LTC4, LTD4 or LTE4 did not induce NF-kappa B activation in 1.3% DMSO-differentiated U-937 cells. Western blotting demonstrated that 10-5 M pranlukast inhibits NF-kappa B activation in 1.3% DMSO-differentiated U-937 and Jurkat cells by about 40% & 30%, respectively. Flow cytometry demonstrated that pranlukast and MK-571 inhibit NF-kappa B activation in 1.3% DMSO-differentiated U-937 and Jurkat cells in a dose-related manner. Moreover, 10-5 M pranlukast and MK-571 inhibited LPS-induced IL-6 production in PBMC by about 65% and 15%, respectively. Conclusion: Pranlukast and MK-571 partially inhibited NF-kappa B activation in 1.3% DMSO-differentiated U-937 and Jurkat cells, and IL-6 release in PBMC. These findings are consistent with the idea that, independently of CysLT1 receptor antagonism, micromolar concentrations of pranlukast suppress the production of proinflammatory cytokines via inhibition of NF-kappa B activation in monocytes/macrophages and T cells, but the contribution of this effect to the anti-inflammatory activity of pranlukast at oral therapeutic doses in asthmatic patients is unclear.[1]

Penicillin (100 U/mL), Streptomycin (100 mg/mL), and 10% heat-inactivated fetal calf serum are added to Dulbecco's modified Eagle's medium (DMEM) for the culture of EA.hy926 cells. The experiments take place 24 hours after the cells are seeded. OGD is executed. In short, the original medium is taken out, and the cells are then put in fresh glucose-free Earle's balanced salt solution (EBSS) after being twice washed with it. After that, cultures are kept in an incubator with 5% CO₂ and 95% N₂ at 37°C for two to eight hours. Normal conditions are maintained for control cultures in EBSS containing glucose. The culture is supplemented with 10 μM Pyrrolidine dithiocarbamate (PDTC), 10 μM Zileuton, a 5-LOX inhibitor, or 10 μM Pranlukast 30 minutes prior to OGD exposure and kept there throughout OGD[2].

Mice: The mice used are male ddY mice. Every mouse that is used is between 7 and 8 weeks old. Mice are given endotoxin shock. To summarize, 24 hours prior to LPS challenge, intraperitoneal (i.p.) injection of CAR (5 mg in 0.5 mL of physiological saline) is administered as a priming agent. The inducing agent, LPS (50 p.g in 0.5 mL of physiological saline), is administered intravenously into the tail vein. Mice are given AA-861, pranlukast (40, 20, and 10 mmol/kg), ethanol, saline, or DMSO subcutaneously (s.c.) in a volume of 1 mL into their backs 30 minutes prior to the LPS provocation. Since peritonitis was caused by CAR i.p. pretreatment, both medications are injected subcutaneously. Before the LPS challenge, 2×10⁵ U of rabbit anti-TNF-a antibody or rabbit normal serum in 0.2 mL is injected intravenously (i.v.) to investigate the function of endogenous TNF in CAR-pretreated mice[3].

Metabolism / Metabolites
Hepatic

[1]. Clin Exp Allergy . 2003 Jun;33(6):802-7.

[2]. Br J Pharmacol . 1998 Jun;124(3):563-71.

[3]. Pharmacology . 2005 Feb;73(2):89-96.

[4]. Brain Res . 2005 Aug 16;1053(1-2):116-25.

N-[4-oxo-2-(2H-tetrazol-5-yl)-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide is a member of chromones.
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It antagonizes or reduces bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.
See also: Pranlukast Hydrate (annotation moved to).

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Drug Indication
Used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists.

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Mechanism of Action
Pranlukast selectively antagonizes leukotriene D₄ (LTD₄) at the cysteinyl leukotriene receptor, CysLT₁, in the human airway. Pranlukast inhibits the actions of LTD₄ at the CysLT₁ receptor, preventing airway edema, smooth muscle contraction, and enhanced secretion of thick, viscous mucus.

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Pharmacodynamics
Pranlukast is a cysteinyl leukotriene receptor-1 antagonist.

C27H23N5O4

481.5026

481.175

C, 67.35; H, 4.81; N, 14.54; O, 13.29

103177-37-3

Pranlukast hemihydrate; 50821-03-7; Pranlukast-d4; 2713172-43-9

4887

White to off-white solid powder

1.4±0.1 g/cm3

236-238ºC

1.681

3.88

2

7

9

36

778

0

O(C1C([H])=C([H])C(=C([H])C=1[H])C(N([H])C1=C([H])C([H])=C([H])C2C(C([H])=C(C3N=NN([H])N=3)OC1=2)=O)=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]

NBQKINXMPLXUET-UHFFFAOYSA-N

InChI=1S/C27H23N5O4/c33-23-17-24(26-29-31-32-30-26)36-25-21(23)10-6-11-22(25)28-27(34)19-12-14-20(15-13-19)35-16-5-4-9-18-7-2-1-3-8-18/h1-3,6-8,10-15,17H,4-5,9,16H2,(H,28,34)(H,29,30,31,32)

N-[4-oxo-2-(2H-tetrazol-5-yl)chromen-8-yl]-4-(4-phenylbutoxy)benzamide

Ono-1078; ONO 1078; ONO-1078; ONO-RS 411; Azlaire; Ono-1078; pranlukast hydrate; ONO 1078; SB 205312; CCN 00401; ONO-RS-411; SB 205312; Pranlukast

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: 11~33.3 mg/mL (22.8~69.2 mM)
H2O: ~0.7 mg/mL (~1.4 mM)

Solubility in Formulation 1: 2.75 mg/mL (5.71 mM) (saturation unknown) 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 sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 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: ≥ 2.75 mg/mL (5.71 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 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 5% DMSO+ 95% Corn oil: 0.6mg/ml (1.25mM)

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