Зафирлукаст

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.

Off-white to pale pink crystalline solid

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

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.

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).

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.