141337-05-5Relevant articles and documents
The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor
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.
, p. 9093 - 9126 (2020)
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.
PYRIDINONE DICARBOXAMIDE FOR USE AS BROMODOMAIN INHIBITORS
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Page/Page column 141; 142, (2017/03/21)
The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
From libraries to candidate: The discovery of new ultra long-acting dibasic β2-adrenoceptor agonists
Alcaraz, Lilian,Bailey, Andrew,Cadogan, Elaine,Connolly, Stephen,Jewell, Robert,Jordan, Stephen,Kindon, Nicholas,Lister, Andrew,Lawson, Mandy,Mullen, Alexander,Dainty, Ian,Nicholls, David,Paine, Stuart,Pairaudeau, Garry,Stocks, Michael J.,Thorne, Phillip,Young, Alan
scheme or table, p. 689 - 695 (2012/03/26)
Libraries of dibasic compounds designed around the molecular scaffold of the DA2/β2 dual agonist sibenadet (Viozan) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β2-agonist with high selectivity and a duration of action commensurable with once daily dosing.
