Abstract
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.
- drug discovery
- enzyme kinetics
- inflammation
- oxidative injury
- oxidative stress
- oxygen radicals
- reactive intermediates
- reactive oxygen species (ROS)
- The American Society for Pharmacology and Experimental Therapeutics