The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex.
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.
Kohrt
Jeffrey T
JT
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.kohrt@pfizer.com
Filipski
Kevin J
KJ
Cody
Wayne L
WL
Cai
Cuiman
C
Dudley
Danette A
DA
Van Huis
Chad A
CA
Willardsen
J Adam
JA
Rapundalo
Stephen T
ST
Saiya-Cork
Kamlai
K
Leadley
Robert J
RJ
Narasimhan
Lakshmi
L
Zhang
Erli
E
Whitlow
Marc
M
Adler
Marc
M
McLean
Kirk
K
Chou
Yuo-Ling
YL
McKnight
Cecile
C
Arnaiz
Damian O
DO
Shaw
Kenneth J
KJ
Light
David R
DR
Edmunds
Jeremy J
JJ
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*
D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; D013925:Thromboplastin; D015942:Factor VIIa