title: The inhibitor of semicarbazide-sensitive amine oxidase, PXS-4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model.
abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death, often induced by cigarette smoking (CS). It is characterized by pulmonary inflammation and fibrosis that impairs lung function. Existing treatments aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A new potential target is the ectoenzyme, semicarbazide-sensitive mono-amine oxidase (SSAO; also known as vascular adhesion protein-1). SSAO is elevated in smokers' serum and is a pro-inflammatory enzyme facilitating adhesion and transmigration of leukocytes from the vasculature to sites of inflammation.
  
  
  
  PXS-4728A was developed as a low MW inhibitor of SSAO. A model of COPD induced by CS in mice reproduces key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. This model was used to assess suppression of SSAO activity and amelioration of inflammation and other characteristic features of COPD.
  
  
  
  Treatment with PXS-4728A completely inhibited lung and systemic SSAO activity induced by acute and chronic CS-exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS-exposure. Therapeutic treatment during chronic CS-exposure, when the key features of experimental COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function.
  
  
  
  Treatment with a low MW inhibitor of SSAO, PXS-4728A, suppressed airway inflammation and fibrosis and improved lung function in experimental COPD, demonstrating the therapeutic potential of PXS-4728A for this debilitating disease.
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.|Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia.
authors: A G
authors: AG
authors: Jarnicki
authors: Drug Discovery Department, Pharmaxis Ltd., Sydney, NSW, Australia.
authors: H
authors: H
authors: Schilter
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors: G
authors: G
authors: Liu
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors: K
authors: K
authors: Wheeldon
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors: A-T
authors: AT
authors: Essilfie
authors: Drug Discovery Department, Pharmaxis Ltd., Sydney, NSW, Australia.
authors: J S
authors: JS
authors: Foot
authors: Drug Discovery Department, Pharmaxis Ltd., Sydney, NSW, Australia.
authors: T T
authors: TT
authors: Yow
authors: Drug Discovery Department, Pharmaxis Ltd., Sydney, NSW, Australia.
authors: W
authors: W
authors: Jarolimek
authors: Centre for Asthma and Respiratory Disease, The University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia. philip.hansbro@newcastle.edu.au.
authors: P M
authors: PM
authors: Hansbro
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology; D012907:Smoking
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C000606296:PXS-4728A; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing)