Design and synthesis of aminophenol-based factor Xa inhibitors.
A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.
Wu
Shung
S
Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, 94804-0099, Richmond, CA, USA
Guilford
William J
WJ
Chou
Yuo-Ling
YL
Griedel
Brian D
BD
Liang
Amy
A
Sakata
Steve
S
Shaw
Kenneth J
KJ
Trinh
Lan
L
Xu
Wei
W
Zhao
Zuchun
Z
Morrissey
Michael M
MM
D000627:Aminophenols / Q000138:chemical synthesis* / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D014961:X-Ray Diffraction
D000627:Aminophenols; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors