title: The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex.
abstract: The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors 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: 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: Lakshmi
authors.initials: L
authors.lastname: Narasimhan
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Kirk
authors.initials: K
authors.lastname: McLean
authors.forename: Yuo-Ling
authors.initials: YL
authors.lastname: Chou
authors.forename: Cecile
authors.initials: C
authors.lastname: McKnight
authors.forename: Damian O
authors.initials: DO
authors.lastname: Arnaiz
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: David R
authors.initials: DR
authors.lastname: Light
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D011517:Prothrombin Time; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; D013925:Thromboplastin; D015942:Factor VIIa