Hydroxyacetophenone-derived antagonists of the peptidoleukotrienes

Abstract

Considerations of the possible similarities between leukotriene D4 and its prototypical antagonist, FPL 55712, led to the development of a new series of leukotriene antagonists incorporating a hydroxyacetophenone group (e.g., the toluic acids 16 and 18). Although considerable attention has focused on FPL 55712-derived analogues, only limited investigations into alternatives for the standard 4-acetyl-3-hydroxy-2-propylphenoxy moiety have been reported. Therefore, an extensive study of modifications to the hydroxyacetophenone portion of toluic acid 18 was undertaken. Although no viable alternative to the 3-hydroxy moiety was discovered, replacements for the 2-propyl group (34, 37) and the 4-acetyl functionality (56, 59) yielded potent antagonists. A number of compounds exhibited longer duration of action in vivo than FPL 55712.

Leukotrienes, Antileukotrienes and Asthma

“…Compared to FPL 55712, four-fold increase in potency and 2.5-fold increase in selectivity was obtained by incorporating an aryl group into the structure and by the addition of a methoxy group to the aryl moiety [64]. The replacement of a carboxylic acid group with a biomimetic tetrazole results in increased potency, as shown by tomelukast, a compound that was withdrawn from clinical study for safety reasons [65].…”

“…Zafirlukast was developed from lipid acid analogs that incorporated structural components from both FPL 55712 and leukotrienes [63,64]. The starting point in the identification of zafirlukast was an indole-containing structure (Fig.…”

2-[4-[Bis(2-chloroethyl)amino]benzyl]-5,5-dimethyl-2,5-dihydro-4H-benzo[e]isoindol-4-one (Cytotoxic Oxonaphthalene-Pyrroles, Part I)

“…As previously published the N-alkylation of 1 [9,10] with BOC-protected 4-aminobenzyl bromide with NaH in DMF afforded selectively 2 [8], following deprotection with trifluoroacetic acid [11] furnished the amine which was treated with ethylene oxide [4]. The resulting diol was converted via its mesylate and subsequent reaction with LiCl [12] to target compound 3.…”

Influence of mesogenic core polarity and position of chains attachment on columnar phase stability

“…1-Nonyl-2-octyloxybenzene was synthesised from 2-nonylphenol (9.9 g) in reduction reaction as for compound (d) (Yield: 84%, 12.6 g (0.038 mol)). The final synthesis of 3-nonyl-4-octyloxyacetophenone (j) was performed according to [51] 2,4-Dioctyloxy-3-nonylacetophenone (k) 1,3-dimethoxy-2-nonylbenzene was obtained from 1,3-dimethoxybenzene in analogous way as described in [53]. 2,4-Dihydroxy-3-nonylacetophenone was synthesised from 1,3-dihydroxy-2-nonylbenzene in a similar way as given in [54].…”