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
  • 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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