693248-55-4Relevant academic research and scientific papers
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)
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).
Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors
Seal, Jonathan T.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Foley, James,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Kruger, Ryan G.,Matteo, Jeanne J.,McCabe, Michael T.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alex,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Taylor, Simon,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Wyce, Anastasia,Zhang, Xi-Ping,Demont, Emmanuel H.
, p. 10772 - 10805 (2021/07/31)
The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.
BENZOFURAN DERIVATIVES AND THEIR USE AS BROMODOMAIN INHIBITORS
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Page/Page column 58, (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.
2,3-DIHYDROBENZOFURANS AS BOROMODOMAIN INHIBITORS
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Page/Page column 54, (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.
PYRAZOLE DERIVATIVES AS BROMODOMAIN INHIBITORS
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Page/Page column 72-73, (2018/09/21)
The present invention is directed to pyrazole derivatives, pharmaceutical compositions comprising the compounds and the use of the compounds or the compositions in the treatment of various diseases
BENZO[B]FURANS AS BROMODOMAIN INHIBITORS
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Page/Page column 70, (2017/11/06)
The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
PYRIDINONE DICARBOXAMIDE FOR USE AS BROMODOMAIN INHIBITORS
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Page/Page column 92, (2017/04/11)
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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, (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.
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.
