Human 122-lipoxygenase inhibitor

Kenyon, V., Chorny, L, Carvajal, W.J., Holman, T.R., and Jacobson, M.P. (2006) Novel human lipoxygenase inhibitors discovered using virtual screening with homology models. Journal of Medicinal Chemistry, 49, 1356-1363. 

Carroll, J. Jonsson, E. N. Ebel, R. Hartman, M. S. Holman, T. R. Crews, R Probing Sponge-Derived Terpenoids for Human 15-Lipoxygenase Inhibitors. J. Org. Chem. 2001, 66, 6847-6851. 

Lu P, Schrag ML, Slaughter DE, et al. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor. Drug Metab Dispos 2003 31(11) 1352-1360. 

Inhalation of peptide leukotrienes has been shovm to induce a reproducible, robust, well-tolerated bronchoconstriction in humans. Because of this, most clinical studies of CysLTl antagonists have begun with an assessment of their in vivo potency through measurement of their ability to inhibit LT-induced bronchoconstriction. Because these studies can be done over a broad time range, they can also be used to determine human pharmacodynamic values. The most frequent measure was the shift in the LT-induced dose-response curve that is produced by a specified dose of a drug at a particular pretreatment time. Friedman (238) has reviewed the pulmonary-oriented clinical results obtained with most of the earlv peptide leukotriene antagonists and lipoxygenase inhibitors. 

Tong WG, Ding XZ, Witt RC, Adrian TE. Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol Cancer Ther. 1 (2002) 929-935. 

TsukadaT, NakashimaK, Shirakawa S. Arachidonate 5-lipoxygenase inhibitors show potent antiproliferative effects on human leukemia cell lines. Biochem Biophys Res Commun. 140 (1986) 832-836. 

Ding, XZ., Iversen, R, Cluck, M.W., Knezetic, J.A., and Adrian, T.E. (1999) Lipoxygenase Inhibitors Abolish Proliferation of Human Pancreatic Cancer Cells, Biochem. Biophys. Res. Com-mun. 261,218-223. 

Haraldsdottir S, GuSlaugsdottir E, Ingolfsdottir K et al (2004) Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro. Planta Med 70 1098-1100... 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

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