Aminoisoquinolines: design and synthesis of an orally active benzamidine isostere for the inhibition of factor XA.
The design, synthesis and SAR of sulfonamidopyrrolidinone fXa inhibitors incorporating a new benzamidine isostere, namely aminoisoquinolines, is described. These inhibitors have higher Caco-2 cell permeability than comparable benzamidines and attain higher levels of exposure upon oral dosing. The most potent member 14b (fXa Ki=6 nM) is selective against other serine proteases of interest (>600 fold).
Choi-Sledeski
Y M
YM
Department of Medicinal Chemistry, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA.
Becker
M R
MR
Green
D M
DM
Davis
R
R
Ewing
W R
WR
Mason
H J
HJ
Ly
C
C
Spada
A
A
Liang
G
G
Cheney
D
D
Barton
J
J
Chu
V
V
Brown
K
K
Colussi
D
D
Bentley
R
R
Leadley
R
R
Dunwiddie
C
C
Pauls
H W
HW
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D004285:Dogs; D065427:Factor Xa Inhibitors; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors