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Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites:  the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure−activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

An indole class of leukotriene synthesis inhibitors, exemplified by MK-886, which does not directly inhibit 5-lipoxygenase, has been shown to bind to an 18-kDa leukocyte membrane protein and to inhibit 5-lipoxygenase membrane translocation. It was demonstrated that the 18-kDa protein is necessary for the cellular activation of leukotriene synthesis and was named 5-lipoxygenase-activating protein (FLAP). We describe here a class of leukotriene synthesis inhibitors based on a quinoline structure, which is structurally distinct from MK-886. However, similar to MK-886, several quinolines are potent inhibitors of cellular leukotriene synthesis but are poor inhibitors of soluble 5-lipoxygenase. To determine whether FLAP is the protein target of leukotriene synthesis inhibitors of the quinoline class, we investigated the ability of these compounds to inhibit photoaffinity labeling of FLAP and to elute FLAP from indole affinity gels. The abilities of the quinoline inhibitors to interact with FLAP correlated well with their abilities to inhibit leukotriene synthesis in human polymorphonuclear leukocytes. L-674,573, a potent quinoline leukotriene synthesis inhibitor, inhibited indole photoaffinity labeling of FLAP in a concentration-dependent manner. In addition, L-674,573 selectively eluted FLAP from indole affinity gels, in contrast to L-671,480, a quinoline that was inactive as an inhibitor of leukotriene synthesis. When human leukocyte membranes were labeled with the indole photoaffinity probe [125I]L-669,083 and immunoprecipitated with a FLAP antibody, the labeling of FLAP was inhibited by L-674,573 but not by L-671,480. These results suggest a direct binding site for the quinoline leukotriene synthesis inhibitors on FLAP and provide further evidence for the essential role of FLAP in cellular leukotriene synthesis.

AbstractAlpha1-acid glycoprotein (AGP) is an immunomodulatory protein expressed by hepatocytes in response to the systemic reaction that follows tissue damage caused by inflammation, infection or trauma. A proteomic approach based on two dimensional electrophoresis, immunoblotting and staining of 2DE gels with dyes specific for post-translational modifications (PTMs) such as glycosylation and phosphorylation has been used to evaluate the differential interspecific protein expression of AGP purified from human, bovine and ovine sera. By means of these techniques, several isoforms have been identified in the investigated species: they have been found to change both with regard to the number of isoforms expressed under physiological condition and with regard to the quality of PTMs (i.e. different oligosaccharidic chains, presence/absence of phosphorilations). In particular, it is suggested that bovine serum AGP may have one of the most complex pattern of PTMs among serum proteins of mammals studied so far.

The various substituted phenylketobutyric acids (VIa) ‐ (VIe) and (VIII) are prepared from the anisoles (Ia) ‐ (Ic) as shown in the reaction scheme.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reaction of the alcohols (I) with the silyl chloride (II) yields the tert‐butoxydiphenylsilyl ethers (III).