In summary we discovered azaindole substituted

In summary, we discovered 7-azaindole substituted -hydroxypyridone as a potent zinc-binding GLO1 inhibitor (IC=11nM) through lead generation from HTS and structure-based inhibitor design. The X-ray cocrystal structure and the comparison of binding energies with the indole counterpart revealed that bound to the water network and its binding was enthalpy-driven. Methoxypropyl chain of is essential for potent activity and this chain seems to stabilize the water network by strengthening neighboring hydrogen bonds. Other approaches of lead optimization for new GLO1 inhibitors will be discussed in future publications. Acknowledgments
Introduction The receptor for advanced glycation end products, RAGE, is involved in the pathogenesis of many diseases, such as diabetes mellitus and its complications [1], cardiovascular diseases [2], chronic renal diseases [3], chronic inflammatory diseases and cancer [4], as well as AGEs. RAGE, a transmembrane receptor and a member of the immunoglobuline superfamily [5] was first described as a receptor for advanced glycation end products [6]. However, RAGE also binds other ligands like proinflammatory S100 proteins/calgranulins, High Mobility Group proteins including HMGB1, amyloid β peptide [7], [8]. RAGE is expressed on cell surface of numerous cell types, e.g. macrophages, monocytes, endothelial cells, neurons, smooth muscles. RAGE–ligand interaction results in the activation of intracellular pathways of nuclear factor κB [5]. Stimulation of RAGE leads to generation of oxidative stress and triggering of inflammatory and proliferative processes followed by tissue injury [9]. Soluble receptor for advanced glycation end products, sRAGE, is the truncated form of RAGE, lacking transmembrane domain. Soluble RAGE has two variants: endogenously secreted RAGE (esRAGE), which is secreted from the jak stat pathway and cleaved RAGE (cRAGE), which is formed by proteolytic cleavage from the cell surface by matrix metalloproteinases. sRAGE might act as a decoy by binding RAGE ligands and so diminishes the pathological effects mediated by RAGE [10]. The gene encoding RAGE is located on chromosome 6p21.3 and comprises 11 exons. Several polymorphisms of RAGE gene are known today. In the centre of interest are particularly and RAGE 557 G/A polymorphisms and polymorphisms are located in the gene promoter and have effect on transcriptional activity. RAGE 2184A/G polymorphism is located on intron 8. sRAGE produced by alternative splicing of RAGE mRNA involves areas between introns 7 and 9, so the RAGE 2184A/G polymorphism is hypothetically located in the regulatory binding site and influences the production of sRAGE. The study confirms that 2184 GG genotype is associated with elevated sRAGE as well as esRAGE serum levels [3]. RAGE 557 G/A polymorphism, also known as Gly82Ser polymorphism, located in exon 3, appears to be important in the regulation of ligand binding. Glyoxalase I, zinc metalloenzyme, metabolizes predominantly glyoxal and methylglyoxal, precursors of AGEs. Decreased glyoxalase I activity leads to enhanced formation of AGEs and thus tissue damage [11], [12]. There is evidence that glyoxalase I activity is decreased by RAGE–S100A12 interaction [12]. The gene encoding glyoxalase I is located on chromosome 6p21.2 and comprises 6 exons. The most studied GLO1 polymorphism A419C results in Ala111Glu change. According to the latest studies the presence of A− allele causes reduced activity of glyoxalase I enzyme [13]. The role of RAGE and sRAGE in pathological pregnancy has already been studied. Several studies demonstrated altered sRAGE serum levels in women with preterm labor [14], [15], preeclampsia [16] or with gestational diabetes mellitus [17]. Affected amniotic fluid sRAGE concentrations were showed in patients with chorioamnitis and preeclampsia as well [18], [19]. Cooke et al. showed in their study an increased expression of RAGE in myometrium of women with preeclampsia [20]. A recent study of Santos et al. focused on RAGE −429 T/C and RAGE −374 T/A polymorphisms in patients with gestational diabetes, though they did not find any association [21]. The role of glyoxalase I in pathological pregnancy was demonstrated in one single study of Sankaralingam, who showed decreased activity of glyoxalase I in the vasculature of women with preeclampsia [22].