281203-98-3Relevant academic research and scientific papers
Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design
Turner, Lewis D.,Summers, Abbey J.,Johnson, Laura O.,Knowles, Margaret A.,Fishwick, Colin W. G.
supporting information, p. 1264 - 1268 (2017/12/26)
Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives. Biological evaluation revealed that these indazole-containing fragments inhibited FGFR1-3 in the range of 0.8-90 μM with excellent ligand efficiencies of 0.30-0.48. Some compounds exhibited moderate selectivity toward individual FGFRs, indicating that further optimization using SBDD may lead to potent and selective inhibitors of the FGFR family.
N-alkylamino-indoles for the treatment of migraine
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, (2008/06/13)
The present invention is directed to compounds useful in the treatment of migraine which have the general formula (II).
