Pyrimidine based Receptor for Advanced Glycation Endproducts (RAGE) inhibitors as an anti-inflammatory compounds

INTRODUCTION:

The interaction between RAGE and its ligands is thought to result in pro-infl ammatory gene activation. RAGE has been linked to several chronic diseases, which are thought to result from vascular damage. The pathogenesis is hypothesized to include ligand binding upon which RAGE signals activation of the nuclear factor kappa B (NF-κB). NF-κB control

TECHNOLOGY (INVENTION) DESCRIPTION:

Receptor for advanced glycation endproducts plays an important role in many pathological processes and thus represents potential for research and development of diagnostic and therapeutic strategies. Although there were several small molecular RAGE inhibitors described in the literature, they mostly do not showed proof-of-concept therapeutic potential, and thus, there is still potential for future developments in the field.

ADVANTAGES OVER EXISTING SOLUTIONS:

We have discovered a group of pyrimidine derivatives with proprietary structure and ability to inhibit RAGE receptor (low micromolar concentrations). The effects were described under in vitro conditions using RAGE ligand (β-amyloid, S-100 protein and glycated albumin) dependent activation of NFκB, MAPK/JNK (AP-1) and JAK/STAT (STATJ) signaling. The binding was further confi rmed and SAR elucidated by docking against the crystal structure of the RAGE. In vitro validation experiments have also demonstrated inhibition of RAGE ligand dependent activation of NO production in macrophages cells co-stimulated with IFN-γ. The compounds have reasonable toxicity, regiments with 50 mg/kg (2-3x daily) or

DEVELOPMENT STATUS (STAGE):

Laboratory scale, data on cell lines, structural data from receptor docking, limited ADME/Tox data, in vivo pharmacology

PUBLICATIONS:

IP PROTECTION STATUS:

Patent protection: Patent protection is scheduled for 2016. For more details a CDA/NDA is required.

TECHNOLOGY / IP OWNERS :

Palacky University Olomouc - Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences Institute of Experimental Medic