2 research outputs found
Discovery of <i>N</i>ā[4-(1<i>H</i>āPyrazolo[3,4ā<i>b</i>]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors
From a virtual screening starting
point, inhibitors of the serum
and glucocorticoid regulated kinase 1 were developed through a combination
of classical medicinal chemistry and library approaches. This resulted
in highly active small molecules with nanomolar activity and a good
overall in vitro and ADME profile. Furthermore, the compounds exhibited
unusually high kinase and off-target selectivity due to their rigid
structure
Identification of High-Affinity P2Y<sub>12</sub> Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone
A series of novel, highly potent P2Y<sub>12</sub> antagonists
as
inhibitors of platelet aggregation based on a phenylpyrazole glutamic
acid piperazine backbone is described. Exploration of the structural
requirements of the substituents by probing the structureāactivity
relationship along this backbone led to the discovery of the <i>N</i>-acetyl-(<i>S</i>)-proline cyclobutyl amide moiety
as a highly privileged motif. Combining the most favorable substituents
led to remarkably potent P2Y<sub>12</sub> antagonists displaying not
only low nanomolar binding affinity to the P2Y<sub>12</sub> receptor
but also a low nanomolar inhibition of platelet aggregation in the
human platelet rich plasma assay with IC<sub>50</sub> values below
50 nM. Using a homology and a three-dimensional quantitative structureāactivity
relationship model, a binding hypothesis elucidating the impact of
several structural features was developed