The de novo design and synthesis of cyclic urea inhibitors of factor Xa: optimization of the S4 ligand.
In this report refinements to the S4 ligand group leads to compound 19, an inhibitor of fXa with good potency in vitro and an improved pharmacokinetic profile in rabbit. The X-ray crystallographic study of a representative analogue confirms our binding model for this series.
Galemmo
R A
RA
DuPont Pharmaceuticals Company, Wilmington, DE 19880-0500, USA. robert.a.galemmo@dupontpharma.com
Wells
B L
BL
Rossi
K A
KA
Alexander
R S
RS
Dominguez
C
C
Maduskuie
T P
TP
Stouten
P F
PF
Wright
M R
MR
Aungst
B J
BJ
Wong
P C
PC
Knabb
R M
RM
Wexler
R R
RR
D000818:Animals; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D008024:Ligands; D008958:Models, Molecular; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014508:Urea / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D008024:Ligands; D015842:Serine Proteinase Inhibitors; D014508:Urea