1,4-Dihydroindeno[1,2-c]pyrazoles with acetylenic side chains as novel and potent multitargeted receptor tyrosine kinase inhibitors with low affinity for the hERG ion channel.
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
Dinges
Jürgen
J
Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. jurgen.dinges@abbott.com
Albert
Daniel H
DH
Arnold
Lee D
LD
Ashworth
Kimba L
KL
Akritopoulou-Zanze
Irini
I
Bousquet
Peter F
PF
Bouska
Jennifer J
JJ
Cunha
George A
GA
Davidsen
Steven K
SK
Diaz
Gilbert J
GJ
Djuric
Stevan W
SW
Gasiecki
Alan F
AF
Gintant
Gary A
GA
Gracias
Vijaya J
VJ
Harris
Christopher M
CM
Houseman
Kathryn A
KA
Hutchins
Charles W
CW
Johnson
Eric F
EF
Li
Hu
H
Marcotte
Patrick A
PA
Martin
Ruth L
RL
Michaelides
Michael R
MR
Nyein
Michelle
M
Sowin
Thomas J
TJ
Su
Zhi
Z
Tapang
Paul H
PH
Xia
Zhiren
Z
Zhang
Henry Q
HQ
D000480:Alkynes / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004958:Estradiol; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007192:Indenes / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011720:Pyrazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014591:Uterine Diseases / Q000139:chemically induced / Q000188:drug therapy; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
C520640:6-((4-methylpiperazin-1-yl)methyl)-3-(5-(3-phenoxyprop-1-ynyl)thiophen-3-yl)-1,4-dihydroindeno(1,2-c)pyrazole; C520641:7-((1H-1,2,4-triazol-1-yl)methyl)-3-(5-(3-(2-methoxyethoxy)prop-1-ynyl)thiophen-3-yl)-1,4-dihydroindeno(1,2-c)pyrazole; D000480:Alkynes; D000970:Antineoplastic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007192:Indenes; C000606913:KCNH2 protein, human; D011720:Pyrazoles; D013876:Thiophenes; D004958:Estradiol; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2