534596-12-8Relevant academic research and scientific papers
Design and synthesis of novel N-sulfonyl-2-indole carboxamides as potent PPAR-γ binding agents with potential application to the treatment of osteoporosis
Hopkins, Corey R.,O'Neil, Steven V.,Laufersweiler, Michael C.,Wang, Yili,Pokross, Matthew,Mekel, Marlene,Evdokimov, Artem,Walter, Richard,Kontoyianni, Maria,Petrey, Maria E.,Sabatakos, Georgios,Roesgen, Jeff T.,Richardson, Eloise,Demuth Jr., Thomas P.
, p. 5659 - 5663 (2007/10/03)
The synthesis and structure-activity relationships of a novel series of N-sulfonyl-2-indole carboxamides that bind to peroxisome proliferator-activated receptor gamma (PPAR-γ) are reported. Chemical optimization of the series led to the identification of 4q (IC50 = 50 nM) as a potent binding agent of PPAR-γ. Also reported is preliminary cell based data suggesting the use of these compounds in the treatment of osteoporosis.
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
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)
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.
Factor Xa inhibitors based on a 2-carboxyindole scaffold: SAR of neutral P1 substituents
Nazare, Marc,Essrich, Melanie,Will, David W.,Matter, Hans,Ritter, Kurt,Urmann, Matthias,Bauer, Armin,Schreuder, Herman,Dudda, Angela,Czech, Joerg,Lorenz, Martin,Laux, Volker,Wehner, Volkmar
, p. 4191 - 4195 (2007/10/03)
A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated with the 2-carboxyindole scaffold. This privileged fragment assembly approach yielded a set of equipotent, selective inhibitors with structurally diverse neutral P1 substituents.
