Benzylamine-based selective and orally bioavailable inhibitors of thrombin.
A series of p-aminomethylphenylalanine derivatives were investigated as novel thrombin inhibitors. This study led to potent inhibitors of thrombin (Ki up to 3.3 nM) that are trypsin-selective, highly orally bioavailable in rats, and highly permeable across Caco-2 cells. The P1 benzylamine binding mode in the thrombin active site was identified by X-ray crystallographic analysis.
Lee
K
K
Biotech Research Institute, LG Chemical Ltd./Research Park, Taejon, Korea.
Jung
W H
WH
Park
C W
CW
Hong
C Y
CY
Kim
I C
IC
Kim
S
S
Oh
Y S
YS
Kwon
O H
OH
Lee
S H
SH
Park
H D
HD
Kim
S W
SW
Lee
Y H
YH
Yoo
Y J
YJ
D000818:Animals; D001596:Benzylamines / Q000737:chemistry*; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D001596:Benzylamines; D015842:Serine Proteinase Inhibitors; C030796:benzylamine; D013917:Thrombin