The s
ynthesis of a novel series of 1,4-dih
ydroindeno[1,2-
c]p
yrazoles with acet
ylene-t
ype side chains isdescribed. Optimization of those compounds as KDR kinase inhibitors identified
8, which displa
yed an oralactivit
y 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 efficac
y in an MX-1 human breast carcinoma xenograft tumor growthmodel (tumor growth inhibition = 90% at 25 mg/kg·da
y po). The compound was docked into a homolog
ymodel of the homo-tetrameric pore domain of the hERG potassium channel to identif
y strategies to improveits cardiac safet
y profile. S
ystematic interruption of ke
y binding interactions between
8 and Phe656, T
yr652,and Ser624
yielded
90, which onl
y showed an IC
50 of 11.6
![](/images/entities/mgr.gif)
M in the hERG patch clamp assa
y. The selectivit
yprofile for
8 and
90 revealed that both compounds are multitargeted receptor t
yrosine kinase inhibitors withlow nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.