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PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis.

Abstract
Small vessel vasculitis is a life-threatening condition and patients typically present with renal and pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by myeloperoxidase (MPO), which generates hypochlorous acid among other oxidants. MPO has been associated with vasculitis, disseminated vascular inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to vascular injury by 1) catabolizing nitric oxide, impairing vasomotor function; 2) causing oxidative damage to lipoproteins and endothelial cells, leading to atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and thrombosis. Here we report a selective 2-thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) and demonstrate that MPO is a critical mediator of vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse peritonitis. The contribution of MPO activity to vasculitis was then examined in an immune complex model of pulmonary disease. Oral administration of PF-1355 reduced plasma MPO activity, vascular edema, neutrophil recruitment, and elevated circulating cytokines. In a model of anti-glomerular basement membrane disease, formerly known as Goodpasture disease, albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases.
AuthorsWei Zheng, Roscoe Warner, Roger Ruggeri, Chunyan Su, Christian Cortes, Athanasia Skoura, Jessica Ward, Kay Ahn, Amit Kalgutkar, Dexue Sun, Tristan S Maurer, Paul D Bonin, Carlin Okerberg, Walter Bobrowski, Thomas Kawabe, Yanwei Zhang, Timothy Coskran, Sammy Bell, Bhupesh Kapoor, Kent Johnson, Leonard Buckbinder
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 353 Issue 2 Pg. 288-98 (May 2015) ISSN: 1521-0103 [Electronic] United States
PMID25698787 (Publication Type: Journal Article)
CopyrightCopyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • 2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide
  • Acetamides
  • Enzyme Inhibitors
  • Pyrimidines
  • Pyrimidinones
  • Peroxidase
Topics
  • Acetamides (pharmacology)
  • Animals
  • Enzyme Inhibitors (pharmacology)
  • Glomerular Basement Membrane (drug effects, pathology)
  • Glomerulonephritis (enzymology, immunology, pathology, prevention & control)
  • Humans
  • Immune Complex Diseases (enzymology, immunology, pathology, prevention & control)
  • Lung (blood supply, drug effects, immunology)
  • Mice
  • Neutrophil Infiltration (drug effects)
  • Peroxidase (antagonists & inhibitors)
  • Pyrimidines (pharmacology)
  • Pyrimidinones (pharmacology)
  • Signal Transduction (drug effects)
  • Vasculitis (enzymology, immunology, pathology, prevention & control)

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