Substituted 1-methyl-4-phenylpyrrolidin-2-ones – Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors

J. P. Hilton-Proctor, O. Ilyichova, Z. Zheng, I. G. Jennings, R. W. Johnstone, J. Shortt, S. J. Mountford, M. J. Scanlon, P. E. Thompson

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N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue – 1-methyl-4-phenylpyrrolidin-2-one – and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.

Original languageEnglish
Article number112120
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Apr 2020


  • BRD4
  • Bromodomain
  • Epigenetics
  • Fragment-based Drug Design
  • K-ac

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