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

Indole-like Trk receptor antagonists

Jaana Tammiku-Taul  1 , Rahel Park  2 , Kaur Jaanson  2 , Kristi Luberg  2 , Dimitar A Dobchev  3 , Dzmitry Kananovich  3 , Artur Noole  3 , Merle Mandel  4 , Allen Kaasik  4 , Margus Lopp  3 , Tõnis Timmusk  5 , Mati Karelson  6
Affiliations

Indole-like Trk receptor antagonists

Jaana Tammiku-Taul et al. Eur J Med Chem. .

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.

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