title: Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research and Development, Chesterfield, MO 63017, USA. john.i.trujillo@pfizer.com
authors.forename: John I
authors.initials: JI
authors.lastname: Trujillo
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Mahoney
authors.forename: Scott
authors.initials: S
authors.lastname: Long
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Garland
authors.forename: Carrie
authors.initials: C
authors.lastname: Kusturin
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Abbas
authors.forename: Michael S
authors.initials: MS
authors.lastname: South
authors.forename: David B
authors.initials: DB
authors.lastname: Reitz
mesh_terms: 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*
chemical_list: D000925:Anticoagulants; D011714:Pyrans; D013925:Thromboplastin; D015942:Factor VIIa