1. Indole-like Trk receptor antagonists.
- Author
-
Tammiku-Taul J, Park R, Jaanson K, Luberg K, Dobchev DA, Kananovich D, Noole A, Mandel M, Kaasik A, Lopp M, Timmusk T, and Karelson M
- Subjects
- Brain cytology, Cell Survival drug effects, Drug Design, Inhibitory Concentration 50, Neurons cytology, Neurons drug effects, Neurons metabolism, Protein Domains, Receptor, trkA chemistry, Receptor, trkA metabolism, Indoles chemistry, Indoles pharmacology, Receptor, trkA antagonists & inhibitors
- Abstract
The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC., (Copyright © 2016. Published by Elsevier Masson SAS.)
- Published
- 2016
- Full Text
- View/download PDF