Systematic substitution of a 2-carboxyindole scaffold led to a highly potent factor Xa inhibitor with a K(i) of 0.07 nM, revealing substituent-dependent switching of the inhibitor binding mode.
The study identifies a highly potent factor Xa inhibitor (K(i) 0.07 nM) and demonstrates that the P1 ligand modifies the binding mode of the entire scaffold, leading to a nonlinear structure-activity relationship.
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 et al. (Sat,) conducted a other in Factor Xa inhibition. 2-carboxyindole-based factor Xa inhibitors was evaluated on Binding affinity (K(i)) and binding mode. Systematic substitution of a 2-carboxyindole scaffold led to a highly potent factor Xa inhibitor with a K(i) of 0.07 nM, revealing substituent-dependent switching of the inhibitor binding mode.