Design, synthesis, and biological evaluation of optimized phthalazine derivatives as hedgehog signaling pathway...

We report herein the design and synthesis of a series of optimized phthalazine compounds as novel hedgehog signaling pathway inhibitors. The 4-methylamino-piperidine moiety of Taladegib was replaced by different four, five or six-membered azacycle or azaspirocycle building blocks. The in vitro Gli-luciferase assay results demonstrate that the scaffold hopping in this region afforded significant influences on Hh pathway inhibition. Pyrrolidin-3-amine moiety was found to be the best linker between pharmacophores phthalazine and fluorine substituted benzoyl group. Meanwhile the optimization of 1-methyl-1H-pyrazol by different aromatic rings was also investigated and the SAR was described. Many new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC₅₀ values. Among these compounds, compound 23b showed the highest inhibitory potency with an IC₅₀ value of 0.17 nM, which was 35-fold more potent than the lead compound Taladegib and 23-fold more potent than the marketed drug Vismodegib. The selected compounds 23a and 23b also possess potent antitumor activities against medulloblastoma cells proliferation in vitro. In vivo efficacy of 23b in a ptch^+/-p53^-/- mouse medulloblastoma allograft model also indicated encouraging results.