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.

Attraktives Chlor: Nichtkovalente Wechselwirkungen zwischen Chlor‐ oder Brom‐Atomen und aromatischen Ringen in Proteinen bieten einen neuen Ansatzpunkt für die Beeinflussung der molekularen Erkennung. Die Einführung dieser Substituenten an spezifischen Positionen zweier Faktor‐Xa‐Inhibitoren erhöht deren freie Bindungsenergie durch die Wechselwirkung mit einer Tyrosineinheit. Das allgemeine Vorkommen dieses Strukturmotivs wird anhand zahlreicher Kristallstukturen und quantenchemischer Rechnungen belegt (siehe Bild).

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The dramatic rise of the twin epidemics, type 2 diabetes and obesity is associated with increased mortality and morbidity worldwide. Based on this global development there is clinical need for anti-diabetic therapies with accompanied weight reduction. From the approved therapies, the injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only class of agents which are associated with a modest weight reduction. Physiological effects of the gastro-intestinal hormone GLP-1 are improvement of glycemic control as well as a reduction in appetite and food intake. Different approaches are currently under clinical evaluation to optimize the therapeutic potential of GLP-1 RAs directed to once-weekly up to once-monthly administration. The next generation of peptidic co-agonists comprises the activity of GLP-1 plus additional gastro-intestinal hormones with the potential for increased therapeutic benefits compared to GLP-1 RAs.

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