151434-99-0Relevant articles and documents
THERAPEUTIC COMPOUNDS
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Paragraph 00177; 00213, (2020/06/10)
The present invention relates to compounds that are Nrf2 activators. The compounds have the structural formula I defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with Nrf2 activation.
DIRECT INHIBITORS OF KEAP1-NRF2 INTERACTION AS ANTIOXIDANT INFLAMMATION MODULATORS
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Paragraph 0444-0445, (2018/06/09)
A method of identifying compounds as direct inhibitors of Keap1-Nrf2 interaction through high-throughput screening and lead development. The direct inhibitors of Keap1-Nrf2 interaction are more specific and free of various undesirable effects than existing indirect inhibitors, and are potential drug candidates of chemopreventive and therapeutic agents for treatment of various diseases or conditions involving oxidative stress and/or inflammation, including but not limited to cancers, diabetes, Alzheimer's, and Parkinson's. Novel compounds are identified and methods of preventing or treating diseases or conditions related to Keap1-Nrf2 interaction activity by use of the novel compounds identified or compositions containing such compounds are also disclosed.
Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides
Yan, Lin-Jie,Wang, Hai-Feng,Chen, Wen-Xue,Tao, Yuan,Jin, Kai-Jun,Chen, Fen-Er
, p. 2249 - 2253 (2016/07/19)
The synthesis of new chloramphenicol-base-derived thiourea organocatalysts, (1S,2R)-12 a–f and (1R,2R)-15 a–c, and their use in the enantioselective alcoholysis of meso-anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)-12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)-15 a–c. This technique was used to synthesize (R)-(?)-baclofen.
Synthesis of cinchona alkaloid sulfonamide polymers as sustainable catalysts for the enantioselective desymmetrization of cyclic anhydrides
Takata, Shohei,Endo, Yuta,Shahid Ullah, Mohammad,Itsuno, Shinichi
, p. 72300 - 72305 (2016/08/09)
The Mizoroki-Heck polymerization of cinchona-based sulfonamide dimers and aromatic diiodides was investigated in the presence of a palladium catalyst, to obtain chiral polymers in high yields. An iodobenzenesulfonamide derivative of a cinchona alkaloid was also polymerized via self-polycondensation under the same reaction conditions. The catalytic activities of these chiral polymers were examined by using them as catalysts in the enantioselective desymmetrization of cyclic anhydrides.
Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex
Jnoff, Eric,Albrecht, Claudia,Barker, John J.,Barker, Oliver,Beaumont, Edward,Bromidge, Steven,Brookfield, Frederick,Brooks, Mark,Bubert, Christian,Ceska, Tom,Corden, Vincent,Dawson, Graham,Duclos, Stephanie,Fryatt, Tara,Genicot, Christophe,Jigorel, Emilie,Kwong, Jason,Maghames, Rosemary,Mushi, Innocent,Pike, Richard,Sands, Zara A.,Smith, Myron A.,Stimson, Christopher C.,Courade, Jean-Philippe
supporting information, p. 699 - 705 (2014/05/06)
An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl) methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently. To dock or not to dock? Nrf2 has become an attractive neuroprotective target, as the Nrf2 pathway provides a natural cell defense mechanism against damage. Targeting its physiological negative modulator Keap1 with small molecules may allow Nrf2 to play its protective role. To this end, an X-ray structure of Keap1 co-crystallised with compound (S,R,S)-1 a was obtained, elucidating its binding mode, which in turn helped to drive the drug design process.
PROCESS OF MAKING PROSTACYCLIN COMPOUNDS WITH LINKER THIOL AND PEGYLATED FORMS
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Paragraph 0189-0190, (2014/09/30)
A process provides for producing chiral prostacyclin derivatives of Formula (I) in high yield from meso anhydrides.
Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction
Hu, Longqin,Magesh, Sadagopan,Chen, Lin,Wang, Lili,Lewis, Timothy A.,Chen,Khodier, Carol,Inoyama, Daigo,Beamer, Lesa J.,Emge, Thomas J.,Shen, Jian,Kerrigan, John E.,Kong, Ah-Ng Tony,Dandapani, Sivaraman,Palmer, Michelle,Schreiber, Stuart L.,Munoz, Benito
, p. 3039 - 3043 (2013/06/27)
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.
A family of novel bifunctional organocatalysts: Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists
Yang, Hong-Jun,Xiong, Fang-Jun,Li, Jie,Chen, Fen-Er
, p. 553 - 558 (2013/07/27)
A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.
Macrocyclic design strategies for small, stable parallel β-sheet scaffolds
Freire, Felix,Gellman, Samuel H.
supporting information; experimental part, p. 7970 - 7972 (2009/12/02)
(Figure Presented) Pairs of short peptide strands can be induced to adopt an antiparallel β-sheet secondary structure in aqueous solution via a macrocyclic constraint, as illustrated by many natural and designedpeptides. We show that an analogous strategy is successful for creation of small units of parallel β-sheet secondary structure in aqueous solution. Cyclization in this case requires nonpeptide segments for N-to -N and C-to-C interstrand linkage. Surprisingly, we find that only one of these segments needs to be preorganized.
A chiral bifunctional sulfonamide as an organocatalyst: Alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides
Honjo, Takashi,Tsumura, Takeshi,Sano, Shigeki,Nagao, Yoshimitsu,Yamaguchi, Kentaro,Sei, Yoshihisa
experimental part, p. 3279 - 3282 (2010/03/05)
Enantioselective alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides with benzyl alcohol catalyzed by a chiral bifunctional sulfonamide was achieved in up to 98% ee at 5 mol% loading. Georg Thieme Verlag Stuttgart - New York.
