Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa.
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Kochanny
Monica J
MJ
Berlex Biosciences, PO Box 4099, Richmond, CA 94804-0099, USA. Monica_Kochanny@berlex.com
Adler
Marc
M
Ewing
Janice
J
Griedel
Brian D
BD
Ho
Elena
E
Karanjawala
Rushad
R
Lee
Wheeseong
W
Lentz
Dao
D
Liang
Amy M
AM
Morrissey
Michael M
MM
Phillips
Gary B
GB
Post
Joseph
J
Sacchi
Karna L
KL
Sakata
Steven T
ST
Subramanyam
Babu
B
Vergona
Ron
R
Walters
Janette
J
White
Kathy A
KA
Whitlow
Marc
M
Ye
Bin
B
Zhao
Zuchun
Z
Shaw
Kenneth J
KJ
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
D000577:Amides; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes