1048962-48-6Relevant academic research and scientific papers
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.
, p. 1581 - 1587 (2020)
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.
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.
5-AMINO-4-HYDROXY-7- (IMIDAZO [1,2-A] PYRIDIN-6- YLMETHYL)-8-METHYL-NONAMIDE DERIVATIVES AND RELATED COMPOUNDS AS RENIN INHIBITORS FOR THE TREATMENT OF HYPERTENSION
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Page/Page column 38, (2008/06/13)
Compounds of the general formula (I) or its salt or a compound in which one or more atoms are replaced by their stable, nonradio-active isotopes, in particular its pharmaceutically acceptable salt; in which X is -CH2-; R1 is a mono- to tetrasubstituted, mono- or bicyclic, unsaturated heterocyclic radical having 1 to 4 nitrogen atoms, R2 is C1-6alkyl or C3-6cycloalkyl; R3 is independently of one another H, C1-6alkyl, C1-6alkoxycarbonyl or C1-6alkanoyl; R4 is C2-6alkenyl, C1-6alkyl, unsubstituted or substituted aryl- C1-6alkyl or C3-8cycloalkyl; R5 is -Lm-R6; L is C1-6alkylene which is optionally substituted by 1-4 halogen, or a linker: formula (II) n = 0, 1 or 2; m = 0 or 1; R6 is a radical composed of 2 cyclic systems selected from bicyclo[x.y.z]alkyl, spiro[o.p]alkyl, mono- or bioxabicyclo[x.y.z]alkyl or mono- or bioxaspiro[o.p]alkyl, all of which may be substituted by 1-3 substituents selected from C1-6alkyl, C1-6alkoxy, cyano, halogen, C1-6alkoxy- C1-6alkyl, hydroxy-C1-6alkyl or dialkylamino, or if m = 0: is also saturated C3-8heterocyclyl which comprises 1-2 oxygen atoms, substituted by 1-3 substituents selected from C1-6alkyl, C1-6alkoxy, cyano, halogen, C1-6alkoxy- C1-6alkyl, hydroxy- C1-6alkyl or dialkylamino, or if m = 1: is also saturated C3-8heterocyclyl which comprises 1-2 oxygen atoms, optionally substituted by 1-3 substituents selected from C1-6alkyl, C1-6alkoxy, cyano, halogen, C1-6-alkoxy-C1-6alkyl, hydroxy-C1-6alkyl or dialkylamino; have renin- inhibiting properties and can be used as medicines for the treatment of hypertension.
