55685-58-0Relevant academic research and scientific papers
Multigram Synthesis of Tetrasubsituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow
Alder, Catherine M.,Gray, Matthew,Huff, Chelsea A.,Manning, Calvin O.,Preston, Alex,Rushworth, Philip,Shuster, Leanna E.,Watson, Robert J.,Wheelhouse, Katherine M. P.,Williams, Glynn D.,Demont, Emmanuel H.
supporting information, p. 365 - 379 (2022/02/10)
This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, extensive optimization of the fluorination step, and high-yielding aminocarbonylation were key to generate the required 50 g of material. The identified new route also represents a robust starting point for further optimization.
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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.
, p. 3249 - 3281 (2021/04/06)
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).
GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family
Preston, Alex,Atkinson, Stephen J.,Bamborough, Paul,Chung, Chun-Wa,Gordon, Laurie J.,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Lewis, Antonia J.,Lugo, David,Messenger, Cassie,Michon, Anne-Marie,Mitchell, Darren J.,Prinjha, Rab K.,Rioja, Inmaculada,Seal, Jon,Taylor, Simon,Thesmar, Pierre,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
supporting information, p. 1581 - 1587 (2020/09/22)
Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.
2,3-DIHYDROBENZOFURANS AS BOROMODOMAIN INHIBITORS
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Page/Page column 53, (2019/04/27)
The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
PYRIDYL DERIVATIVES AS BROMODOMAIN INHIBITORS
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Page/Page column 38-39, (2017/11/04)
The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
3-SUBSTITUTED PYRAZOLES AND USE AS DLK INHIBITORS
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Page/Page column 147; 148, (2014/08/06)
The present invention provides for compounds of Formula (I) and various embodiments thereof, and compositions comprising compounds of Formula (I) and various embodiments thereof. (I) In compounds of Formula I, the groups R1, R2, R3, R4, R5, R6 and R7 have the meaning as described herein. The present invention also provides for methods of using compounds of Formula I and compositions comprising compounds of Formula (I) as DLK inhibitors and for treating neurodegeneration diseases and disorders.
PYRAZOLYLPYRIDINE ANTIVIRAL AGENTS
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Page/Page column 240, (2011/05/06)
Provided are compounds of Formula (I) and/or Formula (II) and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).
