Potent Reversible Inhibition of Myeloperoxidase by Aromatic Hydroxamates

Forbes, Louisa V.; Sjögren, Tove; Auchère, Françoise; Jenkins, David W.; Thong, Bob; Laughton, David L.; Hemsley, Paul; Pairaudeau, Garry; Turner, Rufus; Eriksson, Håkan; Unitt, John; Kettle, Anthony J.

doi:10.1074/jbc.m113.507756

Cited by 90 publications

(77 citation statements)

References 51 publications

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“…The most potent compounds in the series were constrained 2 H -indazole analogues – i.e., containing N 2 — C 3 fused ring systems – with the most potent also incorporating a 1,3-benzodioxole ring. The present data suggests that, like the 2-thioxanthines, 21 the recently described modified hydroxamates, 20 the tetramethyl and tetraethyl nitroxides 40 and targeted MPO-modulating oligopeptide, 41 2 H -indazoles and 1 H -indazolones should be considered for possible therapeutic inhibition of unwarranted MPO activity in inflammatory diseases characterized by episodes of heightened neutrophil activation and convincing evidences of MPO-related pro-oxidative tissue injury. Such investigations will need to take into consideration toxicology and pharmacokinetic activities in complex biological fluids such as plasma, joint fluids, respiratory tract mucus secretions, and in complex inflammatory milieu.…”

Section: Discussionmentioning

confidence: 61%

“…Docking study validation was accomplished through comparative docking of the 5-fluoroindole scaffold described by Soubhye, 22 and HX1 20 bound in the active site of MPO [Figure 1; (PDB ID 4C1M), RMSD docked vs. natural is 1.2 Å]. Also included in the docking studies was 4-aminobenzoic acid hydrazide, the internal control for the assays discussed herein, which consistently displayed an IC 50 of 81 +/− 19 nM.…”

Section: Resultsmentioning

confidence: 99%

“…This is the case even though several promising recent experimental approaches have been designed to therapeutically target pro-oxidative MPO activities. 20,21 …”

Section: Introductionmentioning

confidence: 99%

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Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Roth

Ott²,

Farber

et al. 2014

Bioorganic & Medicinal Chemistry

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Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO:H2O2:HOCl/HOBr system.

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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

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Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Roth

Ott²,

Farber

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Thus, part of the beneficial effects of MPO inhibition may be from increased neurogenesis. While no clinically approved drug is available to specifically inhibit MPO, several preclinical candidates are in development, and one candidate has completed a phase IIa trial (Churg et al, 2012;Forbes et al, 2013;Ward et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke

Kim

Wei

Lee

et al. 2016

J Pharmacol Exp Ther

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The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions, including the subventricular zone (SVZ), dentate gyrus, as well as the non-neurogenic striatum, and cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes, and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether the inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) (MPO 2/2 mice) can increase neurogenesis after transient middle cerebral artery occlusion in mice. ABAH administration increased the number of proliferating bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitor cells (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ, striatum, and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU 1 cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to postischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.

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“…As shown in Figure 3, ABAH nearly fully inhibits activity, and only a small amount of activity is regained upon washing the plate. In contrast, a reversible inhibitor of MPO, 18 salicylhydroxamic acid (SHA), partially inhibited the enzyme, which then regained full activity after washing. Compound 1c and compound 2k also recovered significant activity upon washing.…”

mentioning

confidence: 99%

Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase

Ganesh

Diebold

et al. 2015

ACS Med. Chem. Lett.

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Myeloperoxidase (MPO) is a key antimicrobial enzyme, playing a normal role in host defense, but also contributing to inflammatory conditions including neuroinflammatory diseases such as Parkinson's and Alzheimer's. We synthesized and characterized more than 50 quinazolin-4(1H)-one derivatives and showed that this class of compounds inhibits MPO with IC 50 values as low as 100 nM. Representative compounds showed partially reversible inhibition that was competitive with respect to Amplex Red substrate and did not result in the accumulation of MPO Compound II. Members of this group show promise for therapeutic development for the treatment of diseases in which inflammation plays a pathogenic role.

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Potent Reversible Inhibition of Myeloperoxidase by Aromatic Hydroxamates

Cited by 90 publications

References 51 publications

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke

Thioxo-dihydroquinazolin-one Compounds as Novel Inhibitors of Myeloperoxidase

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