Indole-like Trk receptor antagonists

Jaana Tammiku-Taul; Rahel Park; Kaur Jaanson; Kristi Luberg; Dimitar A Dobchev; Dzmitry Kananovich; Artur Noole; Merle Mandel; Allen Kaasik; Margus Lopp; Tõnis Timmusk; Mati Karelson

doi:10.1016/j.ejmech.2016.06.003

Indole-like Trk receptor antagonists

Eur J Med Chem. 2016 Oct 4:121:541-552. doi: 10.1016/j.ejmech.2016.06.003. Epub 2016 Jun 4.

Authors

Affiliations

¹ University of Tartu, Institute of Chemistry, Ravila 14A, Tartu, 50411, Estonia; Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
² Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia.
³ Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
⁴ University of Tartu, Institute of Biomedicine and Translational Medicine, Department of Pharmacology, Ravila 19, Tartu, 50411, Estonia.
⁵ Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia. Electronic address: tonis.timmusk@ttu.ee.
⁶ University of Tartu, Institute of Chemistry, Ravila 14A, Tartu, 50411, Estonia; Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia. Electronic address: mati.karelson@ut.ee.

PMID: 27318978
DOI: 10.1016/j.ejmech.2016.06.003

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.

Keywords: 2-Oxindole; Antagonist; Fragment-based QSAR; TrkA; TrkB.

MeSH terms

Brain / cytology
Cell Survival / drug effects
Drug Design
Indoles / chemistry*
Indoles / pharmacology*
Inhibitory Concentration 50
Neurons / cytology
Neurons / drug effects
Neurons / metabolism
Protein Domains
Receptor, trkA / antagonists & inhibitors*
Receptor, trkA / chemistry
Receptor, trkA / metabolism

Substances

Indoles
Receptor, trkA