Developing novel classes of protein kinase CK1? inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems

Protein kinase CK1? expression and activity is involved in different pathological situations that include neuroinflammatory neurodegenerative diseases. For this reason, protein has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems resemble adenine of ATP represent optimal scaffolds the development new class competitive inhibitors. In particular, series [1,2,4]triazolo[1,5-c]pyrimidines [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as presence free amino group able to interact with residues hinge region at 5- 7- positions [1,2,4]triazolo[1,5-c]pyrimidine [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or 3-hydroxyphenyl 3,5-dihydroxyphenyl moiety 2- position both nuclei. Molecular modeling studies identified key interactions inhibitor-protein recognition process appropriately fit outlined structure-activity relationship. Considering fact CK1 various pathologies particular central nervous system, interest inhibitors permeable blood-brain barrier represents today an important goal pharmaceutical field. The best potent compound 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 ?M) predicted intermediate ability cross membrane our vitro assay starting point value inhibition develop more derivatives.