- Insights into the modular design of kinase inhibitors and application to Abl and Axl
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Scaffold hopping is a common strategy for generating kinase inhibitors that bind to the DFG-out inactive conformation. Small structural differences in inhibitor scaffolds can have significant effects on potency and selectivity across the kinome, however, these effects are often not studied in detail. Herein, we outline a design strategy to generate an array of DFG-out conformation inhibitors with three different hinge-binders and two DFG-pocket groups. We studied inhibitor selectivity across a large segment of the kinome and elucidated binding preferences that can be used in scaffold hopping campaigns. Using these analyses, we identified two selective inhibitors that display low nanomolar potency against Axl or wild-type and clinically relevant mutants of Abl.
- Johnson, Taylor K.,Lachacz, Eric J.,Lopez-Barcons, Lluis,Merajver, Sofia D.,Phadke, Sameer,Soellner, Matthew B.,Vandecan, Nathalie,Wu, Zhifen
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- HEMOGLOBIN MODIFIER COMPOUNDS AND USES THEREOF
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Described herein are compounds, including pharmaceutically acceptable salts thereof, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, prevent or diagnose blood-based diseases, disorders or conditions.
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Paragraph 00459
(2018/02/28)
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- Synthesis and anti-oomycete activity of novel quinazolin- and benzothiazol-6-yloxyacetamides: Potent aza-analogs and five-ring analogs of quinoline fungicides
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Novel quinazolin- and benzothiazol-6-yloxyacetamides show excellent in vivo activity against the three economically most important Oomycete pathogens Phytophthora infestans, Plasmopara viticola and Pythium ultimum. They are polar analogs of known quinolin-6-yloxyacetamides, which are not active against the soil-borne damping-off disease caused by Pythium ultimum. The Bogert quinazoline synthesis, an almost forgotten heterocyclization technique, proved to be highly useful for the concise construction of required quinazolin-6-ol building blocks.
- Beaudegnies, Renaud,Quaranta, Laura,Murphy Kessabi, Fiona,Lamberth, Clemens,Knauf-Beiter, Gertrud,Fraser, Torquil
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p. 444 - 452
(2016/01/25)
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- Synthesis and Photochromic Characteristics of 1,3-Dihydrospiropyrimidobenzoxazines> and 1,3-Dihydrospirothiazolobenzoxazines>
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Two new series of 1,3-dihydrospiro derivatives were synthesized, the 1,3-dihydrospiropyrimidobenzoxazines> 4-10 and the 1,3-dihydrospirothiazolobenzoxazines> 11-17.These series extend the available range of photochromic properties (rate constant of thermal bleaching, UV/VIS spectrum of the opened coloured form, and photocoloration yield), an interesting feature of variable-transmission materials.The synthesis of these compounds (Scheme 1) required the preliminary synthesis of intermediate β-hydroxy-α-nitrosoheterocycles 18 and 19 (Scheme 2).Important amounts of a coloured, non-photochromic, stable secondary product (see 20) were formed in the condensation in the spiro series.The photochromic characteristics of the new derivatives were determined using a flash-photolysis apparatus coupled to a fast-scanning spectrometer.The role of the heteroatoms in the oxazine moiety and the role of substituents in the indole moiety were investigated quantitatively through the study of the photochromic properties and the solvent effects.The presence of an S-atom gives rise to interesting properties which open up new prospects for synthesis and applications.
- Tardieu, Pascale,Dubest, Roger,Aubard, Jean,Kellmann, Arlette,Tfibel, Francis,et al.
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p. 1185 - 1197
(2007/10/02)
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