2. Academic Validation
  3. 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

  • J Med Chem. 2015 Nov 12;58(21):8513-28. doi: 10.1021/acs.jmedchem.5b00963.
Roger B Ruggeri 1,  Leonard Buckbinder 1,  Scott W Bagley 1,  Philip A Carpino 1,  Edward L Conn 1,  Matthew S Dowling 1,  Dilinie P Fernando 1,  Wenhua Jiao 1,  Daniel W Kung 1,  Suvi T M Orr 1,  Yingmei Qi 1,  Benjamin N Rocke 1,  Aaron Smith 1,  Joseph S Warmus 1,  Yan Zhang 1,  Daniel Bowles 1,  Daniel W Widlicka 1,  Heather Eng 1,  Tim Ryder 1,  Raman Sharma 1,  Angela Wolford 1,  Carlin Okerberg 1,  Karen Walters 1,  Tristan S Maurer 1,  Yanwei Zhang 1,  Paul D Bonin 1,  Samantha N Spath 1,  Gang Xing 1,  David Hepworth 1,  Kay Ahn 1,  Amit S Kalgutkar 1
Affiliations

Affiliation

  • 1 Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
PMID: 26509551 DOI: 10.1021/acs.jmedchem.5b00963
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.

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