5 research outputs found
Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase
Inhibition of monopolar spindle 1 MPS1 kinase represents a novel approach to cancer treatment instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series triazolopyridines and imidazopyrazines . The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10 fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy model
Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure
The
first-in-class soluble guanylate cyclase (sGC) stimulator riociguat
was recently introduced as a novel treatment option for pulmonary
hypertension. Despite its outstanding pharmacological profile, application
of riociguat in other cardiovascular indications is limited by its
short half-life, necessitating a three times daily dosing regimen.
In our efforts to further optimize the compound class, we have uncovered
interesting structure–activity relationships and were able
to decrease oxidative metabolism significantly. These studies resulting
in the discovery of once daily sGC stimulator vericiguat (compound <b>24</b>, BAY 1021189), currently in phase 3 trials for chronic
heart failure, are now reported
Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure
The
first-in-class soluble guanylate cyclase (sGC) stimulator riociguat
was recently introduced as a novel treatment option for pulmonary
hypertension. Despite its outstanding pharmacological profile, application
of riociguat in other cardiovascular indications is limited by its
short half-life, necessitating a three times daily dosing regimen.
In our efforts to further optimize the compound class, we have uncovered
interesting structure–activity relationships and were able
to decrease oxidative metabolism significantly. These studies resulting
in the discovery of once daily sGC stimulator vericiguat (compound <b>24</b>, BAY 1021189), currently in phase 3 trials for chronic
heart failure, are now reported