4-(pyrimidin-2-ylamino)benzamide derivatives: design, synthesis, and hedgehog signaling pathway inhibition study

Hedgehog signaling pathway is a new therapeutic target for interventional cancer treatment. A novel series of 4-(pyrimidin-2-ylamino)benzamide derivatives were designed as hedgehog signaling pathway inhibitors based on our previously reported lead compound 1 and its structure activity relationship. Fourteen compounds were synthesized and the inhibitory effects on hedgehog signaling pathway of these compounds were evaluated. The results demonstrated that all the compounds presented good potency against hedgehog signaling pathway, and compound 8e was the most potent one with an IC₅₀ value of 5.0 nmol·L^-1, more potent than GDC-0449. Likewise, compound 8e displayed improved pharmacokinetic properties.