su-11248 has been researched along with Edema* in 2 studies
2 other study(ies) available for su-11248 and Edema
| Article | Year |
|---|---|
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. Topics: Alkynes; Animals; Antineoplastic Agents; Binding, Competitive; Cell Line; Edema; ERG1 Potassium Channel; Estradiol; Ether-A-Go-Go Potassium Channels; Female; Humans; Indenes; Mice; Mice, Inbred BALB C; Models, Molecular; Patch-Clamp Techniques; Protein Binding; Pyrazoles; Radioligand Assay; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Stereoisomerism; Structure-Activity Relationship; Thiophenes; Uterine Diseases; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays | 2007 |
Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors.
A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)). Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Edema; Estradiol; Female; Humans; Mice; Mice, Inbred BALB C; Mice, SCID; Models, Molecular; NIH 3T3 Cells; Phosphorylation; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Structure-Activity Relationship; Urea; Uterus; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays | 2005 |