1435472-77-7Relevant articles and documents
Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases
Ruggeri, Roger B.,Buckbinder, Leonard,Bagley, Scott W.,Carpino, Philip A.,Conn, Edward L.,Dowling, Matthew S.,Fernando, Dilinie P.,Jiao, Wenhua,Kung, Daniel W.,Orr, Suvi T. M.,Qi, Yingmei,Rocke, Benjamin N.,Smith, Aaron,Warmus, Joseph S.,Zhang, Yan,Bowles, Daniel,Widlicka, Daniel W.,Eng, Heather,Ryder, Tim,Sharma, Raman,Wolford, Angela,Okerberg, Carlin,Walters, Karen,Maurer, Tristan S.,Zhang, Yanwei,Bonin, Paul D.,Spath, Samantha N.,Xing, Gang,Hepworth, David,Ahn, Kay,Kalgutkar, Amit S.
, p. 8513 - 8528 (2015/11/25)
Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.
