Discovery of 1-((6-Aminopyridin-3-yl)Methyl)-3-(4-Bromophenyl)Urea as a Potent, Irreversible Myeloperoxidase Inhibitor
| Autor: | Sally Loi, Lac Lee, Jean Regard, Dominique Custeau, Andrew Patterson, Lin Deng, Julien Papillon, Aimee Reynolds, Tyler Harrison, Micah Hollis-Symynkywicz, Jovita Marcinkeviciene, Lawrence G. Hamann, Anup Patnaik, Xianglin Ren, Jutta Blank, Nigel Casson, Laura Axford, Toshiyuki Honda, Lisa Ames, Lihe Zhang, Martin L. Marro |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Aminopyridines Biological Availability Pharmacology medicine.disease_cause Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Thyroid peroxidase In vivo medicine Animals Humans Enzyme Inhibitors Aorta Peroxidase chemistry.chemical_classification Inflammation biology Chemistry Bioavailability Rats Mice Inbred C57BL 030104 developmental biology Enzyme Myeloperoxidase Urea biology.protein Molecular Medicine 030217 neurology & neurosurgery Oxidative stress Ex vivo |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 367(1) |
| ISSN: | 1521-0103 |
| Popis: | Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease. |
| Databáze: | OpenAIRE |
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