The Journal of pharmacology and experimental therapeutics · 2018
Discovery of 1-((6-Aminopyridin-3-yl)Methyl)-3-(4-Bromophenyl)Urea as a Potent, Irreversible Myeloperoxidase Inhibitor.
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Marro Martin L, Patterson Andrew W, Lee Lac, Deng Lin, Reynolds Aimee, Ren Xianglin, Axford Laura, Patnaik Anup, Hollis-Symynkywicz Micah, Casson Nigel, Custeau Dominique, Ames Lisa, Loi Sally, Zhang Lihe, Honda Toshiyuki, Blank Jutta, Harrison Tyler J, Papillon Julien P N, Hamann Lawrence G, Marcinkeviciene Jovita, Regard Jean B
Аннотация
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.