- Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
- Aylott, Helen E.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alexander,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Seal, Jonathan T.,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
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p. 3249 - 3281
(2021/04/06)
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- A study of enantioselective syntheses by Sharpless asymmetric oxidation for aryl sulfoxides containing oxygen groups at the ortho position
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Abstract: While ortho-alkoxy aryl sulfoxides including various substituents were synthesized by Sharpless asymmetric oxidation reaction, we optimized the reaction conditions and screened better combination of starting materials to obtain high enantioselectivity. The result suggested new information that electron-withdrawing substituents on the aromatic ring have a strong influence upon enantioselectivity of the products. Also, several chiral ligands for Sharpless asymmetric oxidation reaction were evaluated to improve the enantioselectivity. Graphic abstract: High enantioselectivity of ortho-alkoxy aryl chiral sulfoxides have been achieved by Sharpless oxidation reaction using Ti(O-i-Pr)4 and diethyl tartrate under anhydrous condition. In particular, the enantioselctivity of products was influenced by electron-withdrawing substituents on the aromatic ring, such as nitro, ester and aldehyde groups.[Figure not available: see fulltext.]
- Takei, Takanori,Takayama, Jun,Xuan, Meiyan,Tomoda, Misa,Miyamae, Hiroshi,Sakamoto, Takeshi
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- TRICYCLIC COMPOUND AND USE THEREOF
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The present invention relates to: a compound selected from the group consisting of a tricyclic compound having the structure of formula I, a pharmaceutically acceptable salt, an isomer, a solvate and a precursor thereof; and a use thereof. The compound effectively controls GPR40, and thus, can be effectively used for the prophylaxis or treatment of diseases associated with GPR40, for example, diabetes and many other diseases.
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- Efficient synthesis and structure-activity relationship of honokiol, a neurotrophic biphenyl-type neolignan
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Honokiol, a biphenyl-type neolignan, which shows the remarkable neurotrophic effect in primary cultured rat cortical neurons, has been effectively synthesized in 21% yield over 14 steps starting from 5-bromosalicylic acid and p-hydroxybenzoic acid by utilizing Pd-catalyzed Suzuki-Miyaura coupling reaction as a key step. Additionally, the structure-activity relationship between neurite outgrowth-promoting activity and its O-methylated and/or its hydrogenated analogues was examined in the primary cultures of fetal rat cortical neurons, suggesting that 5-allyl and 4′-hydroxyl groups are essential for affecting the neurotrophic activity of honokiol.
- Esumi, Tomoyuki,Makado, Gouki,Zhai, Haifeng,Shimizu, Yasuhiro,Mitsumoto, Yasuhide,Fukuyama, Yoshiyasu
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p. 2621 - 2625
(2007/10/03)
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- Short and efficient synthesis of (+)-subersic acids
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An efficient synthesis of (+)-subersic acid, the unnatural enantiomer, has been achieved from sclareol and p-hydroxybenzoic acid.
- Basabe, Pilar,Diego, Alberto,Delgado, Sergio,Díez, David,Marcos, Isidro S.,Urones, Julio G.
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p. 9173 - 9177
(2007/10/03)
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