Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors.
Inhibitors based on the benzimidazole scaffold showed subnanomolar potency against Factor Xa with 500-1000-fold selectivity against thrombin and 50-100-fold selectivity against trypsin. The 2-substituent on the benzimidazole ring had a strong impact on the FXa inhibitory activity. Crystallography studies suggest that the 2-substituent may have a conformational effect favoring the extended binding conformation.
Zhao
Z
Z
Discovery Research, Berlex Biosciences, Richmond, CA 94804-0099, USA. Spring_Zhao@berlex.com
Arnaiz
D O
DO
Griedel
B
B
Sakata
S
S
Dallas
J L
JL
Whitlow
M
M
Trinh
L
L
Post
J
J
Liang
A
A
Morrissey
M M
MM
Shaw
K J
KJ
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D000925:Anticoagulants; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D014361:Trypsin Inhibitors; D013917:Thrombin