title: 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.
abstract: 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. jurgen.dinges@abbott.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dinges
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Lee D
authors.initials: LD
authors.lastname: Arnold
authors.forename: Kimba L
authors.initials: KL
authors.lastname: Ashworth
authors.forename: Irini
authors.initials: I
authors.lastname: Akritopoulou-Zanze
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: George A
authors.initials: GA
authors.lastname: Cunha
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Diaz
authors.forename: Stevan W
authors.initials: SW
authors.lastname: Djuric
authors.forename: Alan F
authors.initials: AF
authors.lastname: Gasiecki
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
authors.forename: Vijaya J
authors.initials: VJ
authors.lastname: Gracias
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Houseman
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: Michelle
authors.initials: M
authors.lastname: Nyein
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Zhi
authors.initials: Z
authors.lastname: Su
authors.forename: Paul H
authors.initials: PH
authors.lastname: Tapang
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Xia
authors.forename: Henry Q
authors.initials: HQ
authors.lastname: Zhang
mesh_terms: 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
chemical_list: 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