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  • 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.

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.

Journal of medicinal chemistry (2015-10-29)
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
ABSTRACT

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.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
PF-06282999, ≥98% (HPLC)