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Bruel A., Logé C., Tauzia M.-L., de Ravache M., Le Guevel R., Guillouzo C., Lohier J.-F., de Oliveira Santos J. S., Lozach O., Meijer L., Ruchaud S., Bénédetti H. and Robert J.-M.

Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3Kα inhibitors

European Journal of Medicinal Chemistry (2012) 57, 225-233 - doi :

par Frapart - publié le

Abstract :

A series of novel 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles was synthesized through a newly developed approach. All these compounds were evaluated against DYRK1A, CDK5 and PI3Kα and showed promising inhibitory activities against PI3Kα with most IC50 values in the micromolar range. Among them, compound 18 was strongly considered as the most interesting compound with an IC50 value of 0.091 μM. This series exhibited also significant anti-proliferative effects in various human cancer cell lines including those resulting in activation of the PI3K pathway.