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.
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.
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Roger B
RB
Ruggeri
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Leonard
L
Buckbinder
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Scott W
SW
Bagley
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Philip A
PA
Carpino
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Edward L
EL
Conn
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Matthew S
MS
Dowling
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Dilinie P
DP
Fernando
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Wenhua
W
Jiao
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Daniel W
DW
Kung
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Suvi T M
ST
Orr
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Yingmei
Y
Qi
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Benjamin N
BN
Rocke
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Aaron
A
Smith
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Joseph S
JS
Warmus
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Yan
Y
Zhang
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Daniel
D
Bowles
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Daniel W
DW
Widlicka
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Heather
H
Eng
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Tim
T
Ryder
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Raman
R
Sharma
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Angela
A
Wolford
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Carlin
C
Okerberg
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Karen
K
Walters
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Tristan S
TS
Maurer
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Yanwei
Y
Zhang
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Paul D
PD
Bonin
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Samantha N
SN
Spath
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Gang
G
Xing
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
David
D
Hepworth
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Kay
K
Ahn
Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
Amit S
AS
Kalgutkar
D000081:Acetamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar
D000081:Acetamides; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D009195:Peroxidase; C000605149:2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide