title: The discovery of fluoropyridine-based inhibitors of the factor VIIa/TF complex--Part 2.
abstract: The activated factor VII/tissue factor complex (FVIIa/TF) is known to play a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. A fluoropyridine-based series of FVIIa/TF inhibitors was discovered which utilized a diisopropylamino group for binding in the S2 and S3 binding pockets of the active site of the enzyme complex. In this series, an enhancement in binding affinity was observed by substitution at the 5-position of the hydroxybenzoic acid sidechain. An X-ray crystal structure indicates that amides at this position may increase inhibitor binding affinity through interactions with the S1'/S2' pocket.
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.kohrt@pfizer.com
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.forename: Chad A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Narasimhan
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Rapundalo
authors.forename: Kamlai
authors.initials: K
authors.lastname: Saiya-Cork
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Leadley
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D013925:Thromboplastin; D015942:Factor VIIa