The discovery of fluoropyridine-based inhibitors of the factor VIIa/TF complex--Part 2.
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.
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
Narasimhan
Lakshmi S
LS
Zhang
Erli
E
Rapundalo
Stephen T
ST
Saiya-Cork
Kamlai
K
Leadley
Robert J
RJ
Edmunds
Jeremy J
JJ
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*
D004791:Enzyme Inhibitors; D011725:Pyridines; D013925:Thromboplastin; D015942:Factor VIIa