- Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
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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.
- 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
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p. 4623 - 4661
(2021/05/07)
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- Synthetic method for aztreonam mother nucleus
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The invention provides a synthetic method for an aztreonam mother nucleus. The method uses sulfamic acid and ethyl bromoacetate as starting raw materials and produces the aztreonam mother nucleus through a chiral prosthetic group-induced 2+2 addition reaction. The method has the advantages of low price of raw materials and high yield, and does not use the high-risk chemical chlorosulfonic acid.
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- Diastereoselective [4+3] cycloadditions of enantiopure nitrogen-stabilized oxyallyl cations
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Diastereoselective trapping of chiral enantiopure oxyallyl cations by common dienes is reported. Excellent diastereoselectivities were obtained and depending on which auxiliary was used cycloadditions proceeded through a chelated or non-chelated pathway.
- MaGee, David I.,Godineau, Edouard,Thornton, Paul D.,Walters, Michael A.,Sponholtz, Deborah J.
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p. 3667 - 3680
(2007/10/03)
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- Non-peptidyl vasopressin V1a antagonists
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This invention provides methods and 2-(azetidin-2-on-1-yl)acetic acid derivatives for the antagonism of the vasopressin V1areceptor.
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- AN ENANTIOSELECTIVE SYNTHESIS OF LORACARBEF (LY163892/KT3777)
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An enantioselective synthesis of the new, orally absorbable, totally synthetic β-lactam antibiotic, loracarbef(LY163892/KT3777) is described.
- Bodurow, C. C.,Boyer, B. D.,Brennan, J.,Bunnell, C. A.,Burks, J. E.,et al.
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p. 2321 - 2324
(2007/10/02)
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- Process and intermediates for β-lactam antibiotics
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1-Benzyl (or substituted benzyl)-3β-[4(S)-aryloxazolidin-2-one-3-yl]-4β-(2-arylvinyl)azetidin-2-ones are provided via cycloaddition of a 4(S)-aryloxazolidin-2-one-3-ylacetyl halide and an imine formed with a benzylamine and a 3-arylacrolein, e.g. cinnamaldehyde. The azetidinones are useful chiral intermediates in an asymmetric synthesis of 1-carba(1-dethia)-3-hydroxy-3-cephem-4-carboxylic acids and esters and to monocyclic β-lactam antibiotics.
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- 7-acylamino-(or 7-amino)-3-trifluoromethylsulfonyloxy-1-carba(1-dethia)-3-cephem-4-carboxylic acids and esters thereof
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7β-Acylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylic acid antibiotic compounds, esters and salts thereof, and the corresponding 7-amino and protected 7-amino 1-carbacephalosporins are provided. The 3-trifluoromethylsulfonyloxy-substituted 1-carbacephalosporins also are useful in a process for preparing 3-halo-1-carbacephalosporins which comprises reacting a 3-triflate ester with a lithium halide in an aprotic polar solvent.
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- The asymmetric synthesis of β-lactam antibiotics. I. Application of chiral oxazolidones in the Staudinger Reaction
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The reactions of oxazolidone with N-benzylimines proceed with exceptional levels of asymmetric induction to form the cycloadducts. Subsequent dissolving metal reduction affords the homochiral β-lactam derivatives in good overall yield.
- Evans,Sjogren
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p. 3783 - 3786
(2007/10/02)
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