溴尿嘧啶
化学
计算生物学
组合化学
酰胺
药物发现
药效团
立体化学
表观遗传学
生物化学
基因
生物
作者
Helen E. Aylott,Sophie Atkinson,Paul Bamborough,Anna K. Bassil,Chun‐wa Chung,Laurie J. Gordon,Paola Grandi,James R. Gray,Lee A. Harrison,Thomas G. Hayhow,Cassie Messenger,Darren J. Mitchell,Alexander Phillipou,Alex Preston,Rab K. Prinjha,Francesco Rianjongdee,Inmaculada Rioja,Jonathan Seal,Ian D. Wall,Robert J. Watson,James M. Woolven,Emmanuel H. Demont
标识
DOI:10.1021/acs.jmedchem.0c02156
摘要
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).
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