1281776-29-1Relevant academic research and scientific papers
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
BIARYL PYRAZOLES AS NRF2 REGULATORS
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Page/Page column 220; 221, (2017/08/01)
The present invention relates to biaryl pyrazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 regulators.
INDANE AND INDOLINE DERIVATIVES AND THE USE THEREOF AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS
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Page/Page column 53-55, (2016/01/25)
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
Group IV organometallic compounds based on dianionic "pincer" ligands: Synthesis, characterization, and catalytic activity in intramolecular hydroamination reactions
Luconi, Lapo,Rossin, Andrea,Motta, Alessandro,Tuci, Giulia,Giambastiani, Giuliano
, p. 4906 - 4921 (2013/05/21)
Neutral ZrIV and HfIV diamido complexes stabilized by unsymmetrical dianionic N,C,N′ pincer ligands have been prepared through the simplest and convenient direct metal-induced Caryl-H bond activation. Simple ligand modification has contributed to highlight the non-innocent role played by the donor atom set in the control of the cyclometallation kinetics. The as-prepared bis-amido catalysts were found to be good candidates for the intramolecular hydroamination/cyclization of primary aminoalkenes. The ability of these compounds to promote such a catalytic transformation efficiently (by providing, in some cases, fast and complete substrate conversion at room temperature) constitutes a remarkable step forward toward catalytic systems that can operate at relatively low catalyst loading and under milder reaction conditions. Kinetic studies and substrate-scope investigations, in conjunction with preliminary DFT calculations on the real systems, were used to elucidate the effects of the substrate substitution on the catalyst performance and to support the most reliable mechanistic path operative in the hydroamination reaction. Changing the order of the "factors" can (somehow) change the result! Neutral ZrIV and HfIV diamido complexes stabilized by unsymmetrical dianionic N,C,N′-pincer ligands have been prepared (see picture) and successfully employed as good catalyst candidates for the efficient and mild intramolecular hydroamination/cyclization of primary aminoalkenes. Copyright
