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The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Aug 01; Vol. 22 (15), pp. 4979-85. Date of Electronic Publication: 2012 Jun 16. - Publication Year :
- 2012
-
Abstract
- Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Cytochrome P-450 CYP3A metabolism
Female
Half-Life
Humans
Indoles pharmacokinetics
Indoles therapeutic use
Lung drug effects
Lung metabolism
Mice
Neoplasms drug therapy
Piperidines pharmacokinetics
Piperidines therapeutic use
Protein Kinase Inhibitors pharmacokinetics
Protein Kinase Inhibitors therapeutic use
Protein Structure, Tertiary
Rats
Receptor Protein-Tyrosine Kinases metabolism
Structure-Activity Relationship
Transplantation, Heterologous
Drug Design
Indoles chemical synthesis
Piperidines chemical synthesis
Protein Kinase Inhibitors chemical synthesis
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22765894
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.06.029