The synthesis of a novel series of 1,4-dihydroindeno[1,2-
c]pyrazoles with acetylene-type side chains isdescribed. Optimization of those compounds as KDR kinase inhibitors identified
8, which displayed an oralactivity in an estradiol-induced murine uterine edema model (ED
50 = 3 mg/kg) superior to Sutent (ED
50 =9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growthmodel (tumor growth inhibition = 90% at 25 mg/kg·day po). The compound was docked into a homologymodel of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improveits cardiac safety profile. Systematic interruption of key binding interactions between
8 and Phe656, Tyr652,and Ser624 yielded
90, which only showed an IC
50 of 11.6
![](/images/entities/mgr.gif)
M in the hERG patch clamp assay. The selectivityprofile for
8 and
90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors withlow nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.