Amido-(propyl and allyl)-hydroxybenzamidines: development of achiral inhibitors of factor Xa.
The design, synthesis and SAR of amido-(propyl and allyl)-hydroxybenzamidine coagulation factor Xa inhibitors is described. These achiral inhibitors are selective for fXa vis a vis structurally related serine proteases and are readily prepared in 6-7 linear steps. The most potent member 9j (fXa Ki = 0.75 nM) is selective (>1000-fold) and an effective anticoagulant in mammalian plasma.
Gong
Y
Y
Department of Medicinal Chemistry, Rhone-Poulenc Rorer, Collegeville, PA 19426-0107, USA.
Pauls
H W
HW
Spada
A P
AP
Czekaj
M
M
Liang
G
G
Chu
V
V
Colussi
D J
DJ
Brown
K D
KD
Gao
J
J
D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001550:Benzamidines; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors