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 Car

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• 作者：Roger B. Ruggeri ; Leonard Buckbinder ; Scott W. Bagley ; Philip A. Carpino ; Edward L. Conn ; Matthew S. Dowling ; Dilinie P. Fernando ; Wenhua Jiao ; Daniel W. Kung ; Suvi T. M. Orr ; Yingmei Qi ; Benjamin N. Rocke ; Aaron Smith ; Joseph S. Warmus ; Yan Zhang ; Daniel Bowles ; Daniel W. Widlicka ; Heather Eng ; Tim Ryder ; Raman Sharma ; Angela Wolford ; Carlin Okerberg ; Karen Walters ; Tristan S. Maurer ; Yanwei Zhang ; Paul D. Bonin ; Samantha N. Spath ; Gang Xing ; David Hepworth ; Kay Ahn ; Amit S. Kalgutkar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：58
• 期：21
• 页码：8513-8528
• 全文大小：645K
• ISSN：1520-4804

文摘

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鈥檚 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.