Design, Synthesis, And Structure-activity Relationship Of Amine Imidazole-pyridine Derivatives As Potent Smoothened Antagonists

The Hedgehog signaling pathway plays an important role in the period of growth and differentiation of embryo. But in adult its role is limited to tissue maintenance and repairmen. Its inappropriate activation has been linked to kinds of human cancers.Developing hedgehog pathway inhibitor has become a way to treat cancer.Hh signaling pathway consists of Hedgehog(Hh) ligand, Patched(Ptch) and Smoothened(Smo) protein and Gli transcription factor. Most of research targets on Smo.There are many compounds inhibiting Smo in clinical. GDC-0449 is already listed, but it has many disadvantages such as low solubility, strong side effects and it has arisen resistance in patients. We compared amounts of compounds in clinical and drug on the market in recent years. Based on the principles of drug design, we designed and synthesized a new list of compounds with the structure having piperazine-imidazole. We hope to improve physicochemical properties of GDC-0449 as well as maintaining its anticancer activity.Starting from 2-amino pyrazine, we synthesized a list of fragments with esters, amines,amides and reversal amides. We connected these fragments with2’,5’-dichloro-3,5-dimethyl-2,4’-bipyridine to derive the final compounds. The structure-activity relationship of the 29 compounds were discussed, and the most active compounds(IC50 = 0.087 μM) was obtained. This lays a good foundation for us to further optimize the structure-activity relationship.