title: 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.
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Roscoe
authors.initials: R
authors.lastname: Warner
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Roger
authors.initials: R
authors.lastname: Ruggeri
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Chunyan
authors.initials: C
authors.lastname: Su
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Christian
authors.initials: C
authors.lastname: Cortes
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Athanasia
authors.initials: A
authors.lastname: Skoura
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Ward
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Amit
authors.initials: A
authors.lastname: Kalgutkar
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Dexue
authors.initials: D
authors.lastname: Sun
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonin
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Carlin
authors.initials: C
authors.lastname: Okerberg
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Walter
authors.initials: W
authors.lastname: Bobrowski
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Kawabe
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Coskran
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Sammy
authors.initials: S
authors.lastname: Bell
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Bhupesh
authors.initials: B
authors.lastname: Kapoor
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.).
authors.forename: Kent
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Pfizer World Wide Research and Development, Cambridge, Massachusetts (W.Z., R.R., C.S., C.C., A.S., J.W., K.A., A.K., D.S., T.S.M., Y.Z., B.K., L.B.); Department of Pathology, University of Michigan, Ann Arbor, Michigan (R.W., K.J.); and Pfizer World Wide Research and Development, Groton, Connecticut (P.D.B., C.O., W.B., T.K., T.C., S.B.) leonard.buckbinder@pfizer.com.
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050533:Glomerular Basement Membrane / Q000187:drug effects* / Q000473:pathology; D005921:Glomerulonephritis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007105:Immune Complex Diseases / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014657:Vasculitis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C000597959:2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide; D000081:Acetamides; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones; D009195:Peroxidase