- 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 Ki 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,Will, David W.,Matter, Hans,Schreuder, Herman,Ritter, Kurt,Urmann, Matthias,Essrich, Melanie,Bauer, Armin,Wagner, Michael,Czech, J?rg,Lorenz, Martin,Laux, Volker,Wehner, Volkmar
-
p. 4511 - 4525
(2007/10/03)
-
- Heterocyclic indole derivatives and mono- or diazaindole derivatives
-
There is provided a compound represented by the general formula (1): wherein Het represents an optionally substituted heterocyclic group; A1and A2each independently represent —CH═, etc.; A3represents —CH2—, etc.; R1represents a 4-fluorophenyl group, etc.; R2represents an alkyl group; n represents 0, 1 or 2, provided that when A1and A2both are —CH═, A3represents —CH2— or —SO2—, which is an indole derivative or a mono- or diazaindole derivative that has COX-2 inhibitory activity and is useful as a pharmaceutical, such as an anti-inflammatory agent, or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.
- -
-
Page column 50
(2008/06/13)
-
- HETEROCYCLIC INDOLE DERIVATIVES AND MONO- OR DIAZAINDOLE DERIVATIVES
-
Indole derivatives and mono- or diazaindole derivatives represented by general formula (1), pharmaceutically acceptable acid-addition salts or base-addition salts thereof or hydrates of the same which have a COX-2 inhibitory activity and are useful as drugs such as anti-inflammatory agents, wherein Het represents an optionally substituted heterocycle; A1 and A2 independently represent each -CH=, etc.; A3 represents -CH2-, etc.; R1 represents 4-fluorophenyl, etc.; R2 represents alkyl; and n is 0, 1 or 2, provided that when A1 and A2 are both -CH=, then A3 is -CH2- or -SO2-.
- -
-
-
