Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa.
Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem.2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa approximately 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.
Trujillo
John I
JI
Department of Medicinal Chemistry, Pfizer Global Research and Development, Chesterfield, MO 63017, USA. john.i.trujillo@pfizer.com
Huang
Horng-Chih
HC
Neumann
William L
WL
Mahoney
Matthew W
MW
Long
Scott
S
Huang
Wei
W
Garland
Danny J
DJ
Kusturin
Carrie
C
Abbas
Zaheer
Z
South
Michael S
MS
Reitz
David B
DB
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D011714:Pyrans; D013925:Thromboplastin; D015942:Factor VIIa