Recent developments in 5lipoxygenase inhibitors

Julémont, Fabien; Dogné, Jean‐Michel; Laeckmann, Didier; Pirotte, Bernard; Leval, Xavier de

doi:10.1517/13543776.13.1.1

Cited by 6 publications

(5 citation statements)

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“…7). 2 Besides NADPH oxidase, LOX12/15, [258][259][260][261] COX 262,263 , and mitochondrial dysfunction 264,265 can also generate superoxide ion and thus have a role in atherosclerosis progression (Fig. 7).…”

Section: F R E E R a D I C A L A N D N O M E D I A T E D S I G N A mentioning

confidence: 99%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acylCoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets. ß 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 483-544, 2008

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Section: F R E E R a D I C A L A N D N O M E D I A T E D S I G N A mentioning

confidence: 99%

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

Tiwari

Singh

Barthwal

2007

Medicinal Research Reviews

139

120

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“…2 Blocking the lipoxygenase pathway for therapeutic benefit in diseases such as asthma, atherosclerosis, and cancer is an active area of investigation. 3 The lipoxygenases catalyze the regio-and steroselective peroxygenation of the methylene-interrupted unsaturated systems found in natural substrates such as linoleic, linolenic, and arachidonic acids. Remarkably, the products of the catalyzed reaction are conjugated hydroperoxides, compounds with cytotoxic properties.…”

Section: Introductionmentioning

confidence: 99%

“…The eicosanoid products of the lipoxygenase pathway include the leukotrienes, a family of paracrine hormones . Blocking the lipoxygenase pathway for therapeutic benefit in diseases such as asthma, atherosclerosis, and cancer is an active area of investigation …”

Section: Introductionmentioning

confidence: 99%

Interaction between Non-Heme Iron of Lipoxygenases and Cumene Hydroperoxide: Basis for Enzyme Activation, Inactivation, and Inhibition

et al. 2004

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Lipoxygenase catalysis depends in a critical fashion on the redox properties of a unique mononuclear non-heme iron cofactor. The isolated enzyme contains predominantly, if not exclusively, iron(II), but the catalytically active form of the enzyme has iron(III). The activating oxidation of the iron takes place in a reaction with the hydroperoxide product of the catalyzed reaction. In a second peroxide-dependent process, lipoxygenases are also inactivated. To examine the redox activation/inactivation dichotomy in lipoxygenase chemistry, the interaction between lipoxygenase-1 (and -3) and cumene hydroperoxide was investigated. Cumene hydroperoxide was a reversible inhibitor of the reaction catalyzed by lipoxygenase-1 under standard assay conditions at high substrate concentrations. Reconciliation of the data with the currently held kinetic mechanism requires simultaneous binding of substrate and peroxide. The enzyme also was both oxidized and largely inactivated in a reaction with the peroxide in the absence of substrate. The consequences of this reaction for the enzyme included the hydroxylation at C beta of two amino acid side chains in the vicinity of the cofactor, Trp and Leu. The modifications were identified by mass spectrometry and X-ray crystallography. The peroxide-induced oxidation of iron was also accompanied by a subtle rearrangement in the coordination sphere of the non-heme iron atom. Since the enzyme retains catalytic activity, albeit diminished, after treatment with cumene hydroperoxide, the structure of the iron site may reflect the catalytically relevant form of the cofactor.

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“…3,4 Recent studies have implicated 5-LO activity 5-7 in a number of other diseases, including COPD, cancer, osteoporosis, and atherosclerosis, and several reviews have appeared recently highlighting the therapeutic potential of 5-LO inhibition. [8][9][10][11][12][13][14] Many of the currently described inhibitors of 5-LO contain functional groups such as phenol, hydroxamate or N-hydroxyurea and act by a redox mechanism or by chelation of the active site iron. The multiple toxicities and difficulties encountered in developing redox inhibitors of 5-LO have led many research groups to strive to find competitive non-redox inhibitors of this enzyme.…”

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confidence: 99%