Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography.
Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.
Nazaré
Marc
M
Aventis Pharma Deutschland GmbH, a company of the Sanofi-Aventis group, Industriepark Höchst, Frankfurt am Main, Germany. Marc.Nazare@sanofi-aventis.com
Will
David W
DW
Matter
Hans
H
Schreuder
Herman
H
Ritter
Kurt
K
Urmann
Matthias
M
Essrich
Melanie
M
Bauer
Armin
A
Wagner
Michael
M
Czech
Jörg
J
Lorenz
Martin
M
Laux
Volker
V
Wehner
Volkmar
V
D000925:Anticoagulants / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007211:Indoles; D015951:Factor Xa