- Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design
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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.
- Turner, Lewis D.,Summers, Abbey J.,Johnson, Laura O.,Knowles, Margaret A.,Fishwick, Colin W. G.
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supporting information
p. 1264 - 1268
(2017/12/26)
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- Reevaluation of the 2-nitrobenzyl protecting group for nitrogen containing compounds: An application of flow photochemistry
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Photochemistry under continuous flow conditions has many potential benefits for photochemical reactions that are problematic in batch. The 2-nitrobenzyl moiety is a photolabile protecting group for nitrogen. However, N-deprotection is generally impractical and, therefore, has not been extensively adopted. This Letter reports significant improvements in the N-deprotection of the 2-nitrobenzyl group through the application of continuous flow photolysis. This procedure was applied to a variety of substrates including indoles, indazoles, pyrazoles and secondary amines. Significant improvement in yield, reaction time and scalability was observed under continuous flow conditions.
- Wendell, Chloe I.,Boyd, Michael J.
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supporting information
p. 897 - 899
(2015/02/05)
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- Scope of the suzuki-Miyaura cross-coupling reactions of potassium heteroaryltrifluoroborates
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A wide variety of bench-stable potassium heteroaryltrifluoroborates were prepared, and general reaction conditions were developed for their cross-coupling to aryl and heteroaryl halides. The cross-coupled products were obtained in good to excellent yields. This method represents an efficient and facile installation of heterocyclic building blocks onto preexisting organic substructures.
- Molander, Gary A.,Canturk, Belgin,Kennedy, Lauren E.
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supporting information; experimental part
p. 973 - 980
(2009/07/11)
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- A versatile method for suzuki cross-coupling reactions of nitrogen heterocycles
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(Chemical Equation Presented) A wide-ranging study of Suzuki reactions which use nitrogen-containing heterocycles is described (see scheme; dba = dibenzylideneacetone, Cy = cyclohexyl). This method is highly versatile (a single procedure was used for all substrates, including boronate esters and trifluoroborates), compatible with a variety of unprotected functionalities (e.g., NH2-and OH-substituted substrates), and efficient even with unactivated aryl chlorides.
- Kudo, Noriaki,Perseghini, Mauro,Fu, Gregory C.
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p. 1282 - 1284
(2007/10/03)
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- 3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a Novel Series of Platelet Activating Factor Antagonists
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(2RS,4R)-3-(2-(3-pyridinyl)thiazolidin-4-oyl)indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compounds were prepared by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidin-4-oyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships observed for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
- Sheppard, George S.,Pireh, Daisy,Carrera, George M.,Bures, Mark G.,Heyman, H. Robin,et al.
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p. 2011 - 2032
(2007/10/02)
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