title: Benzimidazole-based fXa inhibitors with improved thrombin and trypsin selectivity.
abstract: Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.
authors.affiliation: Medicinal Chemistry, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, 94804-0099, Richmond, CA, USA
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: William J
authors.initials: WJ
authors.lastname: Guilford
authors.forename: Brian D
authors.initials: BD
authors.lastname: Griedel
authors.forename: Steve
authors.initials: S
authors.lastname: Sakata
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Shung
authors.initials: S
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Zuchun
authors.initials: Z
authors.lastname: Zhao
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D014357:Trypsin / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin