Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability.
We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.
Riggs
Jennifer R
JR
Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. jennifer.riggs@yahoo.com
Kolesnikov
Aleksandr
A
Hendrix
John
J
Young
Wendy B
WB
Shrader
William D
WD
Vijaykumar
Dange
D
Stephens
Robin
R
Liu
Liang
L
Pan
Lin
L
Mordenti
Joyce
J
Green
Michael J
MJ
Sukbuntherng
Juthamas
J
D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000578:Amidines; D002219:Carbamates; D011355:Prodrugs; D015942:Factor VIIa