T
he synt
hesis of a novel series of 1,4-di
hydroindeno[1,2-
c]pyrazoles wit
h acetylene-type side c
hains isdescribed. Optimization of t
hose compounds as KDR kinase in
hibitors identified
8, w
hic
h 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 s
howed potent antitumor efficacy in an MX-1
human breast carcinoma xenograft tumor growt
hmodel (tumor growt
h in
hibition = 90% at 25 mg/kg·day po). T
he compound was docked into a
homologymodel of t
he
homo-tetrameric pore domain of t
he
hERG potassium c
hannel to identify strategies to improveits cardiac safety profile. Systematic interruption of key binding interactions between
8 and P
he656, Tyr652,and Ser624 yielded
90, w
hic
h only s
howed an IC
50 of 11.6
![](/images/entities/mgr.gif)
M in t
he
hERG patc
h clamp assay. T
he selectivityprofile for
8 and
90 revealed t
hat bot
h compounds are multitargeted receptor tyrosine kinase in
hibitors wit
hlow nanomolar potencies against t
he members of t
he VEGFR and PDGFR kinase subfamilies.