Benzimidazole-based fXa inhibitors with improved thrombin and trypsin selectivity.
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.
Shaw
Kenneth J
KJ
Medicinal Chemistry, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, 94804-0099, Richmond, CA, USA
Guilford
William J
WJ
Griedel
Brian D
BD
Sakata
Steve
S
Trinh
Lan
L
Wu
Shung
S
Xu
Wei
W
Zhao
Zuchun
Z
Morrissey
Michael M
MM
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*
D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D014357:Trypsin; D013917:Thrombin