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Eurostars project reaches unique Not-4 inhibitors

The Eurostar supported project ”Neuroprotective therapy for ischemic stroke” a collaboration between Glucox Biotech AB (GB) and prof. Harald Schmidt at Maastricht University (UM) is approaching its finalization.

Early restoration of cerebral blood is essential to minimize brain damage that will occur in an ischemic stroke event.  The paradox that more damage occurs at the return of the blood flow is well known. Prof. Harald Schmidt has previously demonstrated the importance of enhanced NADPHoxidase 4 (Nox4) activity, in this pathological event, generating reactive oxygen which aggravates tissue damage and brain damage.

Thus a pharmaceutical that efficiently and selective inhibits Nox4 over activity is a hot candidate to minimize the brain damage that will occur in an ischemic stroke.

From GBs portfolio of Nox4 inhibitors four structurally different hits GLX481304, GLX351322, GLX351320, GLX701313 has been developed in a SAR medicinal program (GB) and tested in in vitro/in vivo-stroke models (UM).

The two SAR developed Nox4 inhibitors GLX7013114 and GLX7013107 originating from the hit GLX701313 demonstrate the highest selectivity to Nox4 inhibition in relation to other Nox-isoforms and are presently the most important Nox4 inhibitors in this project. These inhibitors demonstrate neuroprotective effect in two different in vitro stroke models at UM:”Hippocampal Brain Slices” (HBS) and ”Human Brain Micro vascular Endothelial Cells” (HBMEC) that were subjected to oxygen and glucose deprivation.  FTIA without adverse effects and PK results provided the foundation of on-going in vivo study in mice stroke models.

The table show efficiency of the inhibitory action and selectivity in whole cell-assays expressing Nox-isoforms, and also the lack of ability to inhibit Xanthine Oxidase (XO). No endogenous redox activity of the two compounds was detected.

Nox4 IC50 mM Nox1IC50 mM Nox2IC50 mM Nox5IC50 mM XOIC50 mM Endogenous redox activity
GLX7013114 0.3 22 >200 >200 >200 0
GLX7013107 2.4 44 >200 >200 >200 0

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