The de novo design and synthesis of cyclic urea inhibitors of factor Xa: initial SAR studies.
In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.
Galemmo
R A
RA
DuPont Pharmaceuticals Company, Wilmington, DE 19880-0500, USA.
Maduskuie
T P
TP
Dominguez
C
C
Rossi
K A
KA
Knabb
R M
RM
Wexler
R R
RR
Stouten
P F
PF
D001665:Binding Sites; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D011487:Protein Conformation; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D007093:Imidazoles; D011744:Pyrimidinones; D015842:Serine Proteinase Inhibitors; D014508:Urea