- The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor
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The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
- Seal, Jonathan T.,Atkinson, Stephen J.,Aylott, Helen,Bamborough, Paul,Chung, Chun-Wa,Copley, Royston C. B.,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Lindon, Matthew,Messenger, Cassie,Michon, Anne-Marie,Mitchell, Darren,Preston, Alex,Prinjha, Rab K.,Rioja, Inmaculada,Taylor, Simon,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
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p. 9093 - 9126
(2020/10/19)
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- PYRAZOLE DERIVATIVES AS BROMODOMAIN INHIBITORS
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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
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Page/Page column 51
(2018/09/21)
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- PYRIDINONE DICARBOXAMIDE FOR USE AS BROMODOMAIN INHIBITORS
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The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
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Page/Page column 65
(2017/03/21)
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- PYRIDINONE DICARBOXAMIDE FOR USE AS BROMODOMAIN INHIBITORS
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The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
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Page/Page column 53
(2017/04/11)
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- 2-OXO-1,2-DIHYDROPYRIDINE-3,5-DICARBOXAMIDE COMPOUNDS AS BROMODOMAIN INHIBITORS
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The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy
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Page/Page column 45
(2017/07/29)
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- Convenient synthesis of chiral tryptophan derivatives using Negishi cross-coupling
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A facile synthetic procedure for chiral tryptophan derivatives using Negishi cross-coupling reaction of serine-derived iodoalanine with 3-haloindole is described. The best result was obtained when the reaction of N-tosyl-3-bromoindole with N-Cbz-iodoalani
- Tanaka, Minoru,Hikawa, Hidemasa,Yokoyama, Yuusaku
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experimental part
p. 5897 - 5901
(2011/09/19)
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- A total synthesis of (±)-α-cyclopiazonic acid using a cationic cascade as a key step
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The indole alkaloid α-cyclopiazonic acid 1 has been synthesised by a route, which features at its core an acid-catalysed cationic cascade cyclisation terminated by a sulfonamide group.
- Griffiths-Jones, Charlotte M.,Knight, David W.
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experimental part
p. 8515 - 8528
(2011/11/29)
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- Short step synthesis of 4-substituted indoles using palladium-catalyzed C-C bond forming reaction
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Enol triflate of N-tosyl-4-oxo-tetrahydroindole (2) was a good precursor for a synthesis of 4-substituted indoles. Various functional groups were introduced to form corresponding indoles using palladium-catalyzed carbonylation and a cross-coupling reaction followed by dehydrogenation by palladium on charcoal.
- Doi, Kazuyuki,Mori, Miwako
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p. 113 - 116
(2007/10/02)
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- Palladium-Catalyzed Coupling of 2-Bromoanilines with Vinylstannanes. A Regiocontrolled Synthesis of Substituted Indoles
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The palladium-catalyzed cross-coupling reaction of aryl halides and triflates with vinylstannane reagents has been used to produce a variety of substituted indoles.The mild reaction conditions and selectivity inherent in the coupling reaction have been utilized to produce regiochemically pure 4-, 5-, and 6-substituted indoles.
- Krolski, Michael E.,Renaldo, Alfred F.,Rudisill, Duane E.,Stille, J. K.
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p. 1170 - 1176
(2007/10/02)
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- Pharmacologically active 3-substituted beta-carbolines useful as tranquilizers
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3-Substituted beta-carbolines of the formula STR1 wherein RA is H, F, Cl, Br, I, NO2, CN, CH3, CF3, SCH3, NR16 R17 or NHCOR16, wherein R16 and R17/sup
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- Pharmacologically active 3-substituted beta-carbolines
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3-substituted beta-carbolines of the formula STR1 wherein R C is hydrogen, lower alkyl, alkoxyalkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atoms, aralkyl of up to 8 C-atoms, or (CH 2) n OR 20wherein R 20 is alkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-a
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