Zileuton synthesis

The effects of leukotrienes can be blocked at several levels. Inhibitors of FLAP or 5-LO inhibit LT synthesis at all levels. However, FLAP antagonists developed to date have been too hepatotoxic for human use. Zileuton, a 5-LO synthase inhibiting drug, also demonstrated some hepatotoxicity in a small percentage of patients, which was nonetheless entirely reversible. However, the short half-life of this compound requires four times daily... 

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

Zileuton (Zyflo) is an inhibitor of leukotriene synthesis. The dose of zileuton tablets is 600 mg four times daily with meals and at bedtime. The recommended dose of zileuton extended-release tablets is two 600-mg tablets twice daily, within 1 hour after morning and evening meals (total daily dose 2,400 mg). 

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLTi receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinfiammatory activity. The CysLTi-receptor antagonists alter neither the production nor the actions of leukotriene B4. 

Zileuton Inhibits lipoxygenase, reduces synthesis of leukotrienes ... 

Leukotriene inhibitors, one leukotriene inhibitor blocks leukotriene synthesis by inhibiting the action of 5-lipooxygenase (Zileuton Zyflo). Another blocks leukotriene receptors on the surface of smooth-muscle cells and eosinophils (Montelukast Singulair). 

New asthma drugs act by blocking the synthesis of leukotriene C4 from arachidonic acid. For example, zileuton (trade name Zyflo) inhibits the enzyme (called a lipoxygenase) needed for the first step of this process. By blocking the synthesis of leukotriene C4, a compound responsible for the disease, zileuton treats the cause of asthma, not just its symptoms. 

Dube LM, Swanson LJ, Awni W. Zileuton, a leukotriene synthesis inhibitor in the management of chronic asthma. Clinical pharmacokinetics and safety. Chn Rev AUergy Immunol 1999 17(1-2) 213-21. 

Hydroxytyrosol potently inhibited the synthesis of leukotriene B4 and its metabolites 20-hydroxy and 20-carboxy LTB4 in calcium-ionophore stimulated human PMN leukocytes. IC50 was 1.2 pM zileuton used as reference compound had an IC50 of 1.5 pM [81]. Inhibition of 5- and 12-lipoxygenases from rat platelets and leukocytes by hydroxytyrosol was shown by Kohyama et al [79]. These authors compaired the inhibition by hydroxytyrosol with other related phenols present in olive oil (tyrosol. 

Two clinically distinct cysteinyl leukotriene receptor antagonists (zafirlukast and montelukast) and one inhihitor of leukotriene synthesis (zUeuton) have been available in the United States since 1996 for both children and adults with persistent asthma. In challenge studies, they reduce allergen-, exercise-, cold-air hyperventilation-, irritant-, and aspirin-induced asthma. Chnical use of zileuton is limited owing to the need for four-times-daily dosing, the potential for elevated liver enzymes (especially in the first 3 months of therapy), and the potential inhibition of drugs metabolized by the CYP3A4 isoenzymes. ... 

Figure VI-1-3 presents the pathways for the synthesis of PGe, PGE]( PGE2, PGF2a, IX Aj, and the i leukotrienes from the membrane phospholipids. It also shows the sites of action of the corticosteroids, i NSAIDS, COX 2 inhibitors, zileuton and zafirlukast, and other "-lukasts."...

Leukotriene-synthesis inhibitors The formation of leukotrienes depends on lipoxygenation of arachidonic acid by 5-lipoxygenase. Zileuton is a potent and selective inhibitor of 5-lipoxygenase activity and thus inhibits the formation of all 5-lipoxygenase products. Thus, in addition to... 

A modification of the Fiesselman synthesis was used to produce a 5-substituted benzothiophene from the corresponding benzaldehyde derivative as illustrated below. This methodology was also employed in the synthesis and study of zileuton analogues as anti-inflammatory and anti-nocieptive agents." ... 

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