Description
Accolate was launched in Ireland, Finland and the US for treatment of
asthma. Prepared via an eight step synthesis from methyl 3-methoxy-4-
methylbenzoate, zafirlukast acts as a LTD4 antagonist and is the first compound of a
new class of drugs. LTC4, LTD4 and LTE4 were determined to be the constituents of
the slow-reacting substance of anaphylaxis (SRS-A) which was found to induce
asthma effects (bronchoconstriction, increased vascular permeability resulting in
edema, cellular infiltration of airway tissues and decreased mucociliary transport).
Thus an inhibitor of their synthesis would at least attenuate these symptoms.
Zafirlukast binds to the CysLT receptor LT-1 and blocks the effect of LTC4, LTD4 and
LTE4. The drug is an oral twice daily formulation that reversed an LTD4 challenge,
attenuated the response of platelet-activating factor (PAF), an allergen and cold air
challenge and exercise-induced asthma.
Chemical Properties
Off-white to pale pink crystalline solid
Uses
Zafirlukast has been used to stimulate pancreatic β cell line (MIN6) and pancreatic islets for insulin secretion assay. It may be used as an adenosine triphosphate-binding cassette transporter (ABCG2) inhibitor in MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay in human embryonic kidney cells (HEK293) and in Kirby-Bauer disc diffusion assays, bactericidal activity and minimal inhibitory concentration (mIC) assay against M. smegmatis
Uses
A potent, selective and orally active CysLT receptor antagonist. Leukotriene D4 antagonist. Used as an antiasthmatic
Uses
antiasthmatic;leukotriene receptor antagonist (LTRA)
Definition
ChEBI: Zafirlukast is a member of indoles, a carbamate ester and a N-sulfonylcarboxamide. It has a role as an anti-asthmatic agent and a leukotriene antagonist.
Manufacturing Process
6-Nitroindol with 4-bromobenzyl-3-methoxy-benzoic acid methyl ester gives in
presence of silver oxide catalyst the diarilmethane 2-(2,4-dimethoxy-benzyl)-
5-nitro-1H-indole. The indole nitrogen is then converted to its anion with
sodium hydride; treatment with methyl iodide gives the corresponding N-
methyl derivative. Catalitic hydrogenation then converts the nitro group to the
amine to give 4-(6-amino-1H-inden-2-ylmethyl)-3-methoxy-benzoic acid
methyl ester. Acylation of that amine with cyclophentylchloroformate then
gives the urethane [2-(2,4-dimethoxy-benzyl)-1-methyl-1H-indol-5-yl]-
carbamic acid cyclopentyl ester. The benzoate ester is then selectively cleaved
with lithium hydroxide in dimethyl formamide to the corresponding carboxylic
acid. The intermediate is converted to the acyl sulfonamide by coupling with
ortho-toluenesulfonamide to give [2-(2-methoxy-4-o-
tolylmethanesulfonylaminocarbonyl-benzyl)-1-methyl-1H-indol-5-yl]-carbamic
acid cyclopentyl ester (zafirlucast).
Brand name
Accolate (AstraZeneca).
Therapeutic Function
Anti-asthmatic
Acquired resistance
Zafirlukast inhibits CYP3A4 and
CYP2C9 in concentrations equivalent to clinical plasma levels and, therefore, should be used
with caution in patients taking drugs metabolized by these enzymes. Specifically,
coadministration with warfarin results in a significant increase in prothrombin time. Other drugs
metabolized by CYP2C9 are phenytoin and carbamazepine. In
addition, CYP3A4-metabolized drugs are cyclosporine, cisapride, and the dihydropyridine class of
calcium channel blockers. Of particular interest is the fact that aspirin increases the plasma
levels of zafirlukast, and theophylline decreases the plasma levels of zafirlukast. Care should be
taken when coadministering with erythromycin, because this decreases the bioavailability of
zafirlukast.
Biochem/physiol Actions
Zafirlukast plays a key role in alleviating mucus and airway constriction in asthma based inflammatory response. It regulates pancreatic β cells for the secretion of insulin and this functionality is interlinked to the calcium based phosphorylation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase B (AKT). Zafirlukast has inhibitory potential on ATP-binding cassette (ABC) transporters and reverses the multidrug resistance function of ATP-binding cassette super-family G member 2 (ABCG2). Zafirlukast inhibits mycobacterial nucleoid-associated protein Lsr2 and halts the growth of Mycobacteria.
Clinical Use
Zafirlukast is an indole derivative with a sulfonamide group that fulfills the need for an ionizable
moiety on the pharmacophore. A large number of analogues have been prepared; however, they
all resulted in a decrease in antagonist activity. Zafirlukast, like montelukast, is a selective
antagonist for the cysLT1 receptor and antagonizes the bronchoconstrictive effects of all
leukotrienes (LTC4, LTD4, and LTE4).
Veterinary Drugs and Treatments
While zafirlukast potentially could be useful in treating feline asthma,
including allowing dose reductions of corticosteroid therapy,
its efficacy has been disappointing to this point and most do not
recommend its use. Potentially, it could be of benefit in allergymediated
(where leukotrienes play a role) dermatologic conditions, such as atopy in dogs, but evidence has been that it is not
very effective.
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline: possibly increases aminophylline
concentration; zafirlukast concentration reduced.
Analgesics: concentration increased by aspirin.
Antibacterials: concentration reduced by
erythromycin.
Anticoagulants: may enhance the effects of warfarin.
Theophylline: possibly increases theophylline
concentration; zafirlukast concentration reduced.
Metabolism
Zafirlukast is well absorbed orally; however, food will
decrease its absorption by as much as 40%. Zafirlukast is primarily metabolized in the liver by
CYP2C9 and CYP3A4 to hydroxylated metabolites. Zafirlukast also has been shown to
undergo carbamate hydrolysis, followed by N-acetylation. Additionally, zafirlukast in known to
produce an idiosyncratic hepatotoxicity in susceptible patients. This is appears to result from the
formation of an electrophilic α,β-unsaturated iminium intermediate evidenced by the formation of
a glutathione adduct on the methylene carbon bridging the indole ring to the methoxybenzene
moiety of the molecule. More than 90% if its metabolites are
excreted in the feces, with the remaining found in the urine.
References
1) Adkins and Brogden, (1998), Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma; Drugs, 55 121
2) Woszczek et al., (2010), Concentration-dependent noncysteinyl leukotriene type 1 receptor-mediated inhibitory activity of leukotriene receptor antagonists; J. Immunol. 184 2218
3) Wyttenbach & Kuentz (2017), Glass-forming ability of compounds in marketed amorphous drug products; Eur. J. Pharm. and Biopharm., 112 204 [Focus Citation]
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