51145-57-4Relevant articles and documents
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.
INDAZOLES AND AZAINDAZOLES AS LRRK2 INHIBITORS
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Page/Page column 347, (2021/01/29)
The present invention is directed to indazole and azaindazole compounds which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
Fused tetracyclic compounds and application thereof in medicines
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Paragraph 0512; 0530-0532, (2020/04/17)
The invention relates to fused tetracyclic compounds and an application thereof in medicines, and in particular, relates to the application of the fused tetracyclic compounds as medicines for treatingand/or preventing hepatitis B. Specifically, the invention relates to the compounds represented by a general formula (I) or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, wherein the variables are defined in the specification. The invention further relates to the application of the compounds represented by the general formula (I) or the stereoisomers, the tautomers, the nitric oxides, the solvates, the metabolites, the pharmaceutically acceptable salts or the prodrugs thereof as medicines, and in particular, relates tothe application of the compounds as the medicines for treating and/or preventing hepatitis B.
