title: Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability.
abstract: 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.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. jennifer.riggs@yahoo.com
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Riggs
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kolesnikov
authors.forename: John
authors.initials: J
authors.lastname: Hendrix
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.forename: William D
authors.initials: WD
authors.lastname: Shrader
authors.forename: Dange
authors.initials: D
authors.lastname: Vijaykumar
authors.forename: Robin
authors.initials: R
authors.lastname: Stephens
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Joyce
authors.initials: J
authors.lastname: Mordenti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Green
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
mesh_terms: 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
chemical_list: D000578:Amidines; D002219:Carbamates; D011355:Prodrugs; D015942:Factor VIIa