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

  • Eur J Med Chem. 2020 Apr 1;191:112120. doi: 10.1016/j.ejmech.2020.112120.
J P Hilton-Proctor  1 ,  O Ilyichova  1 ,  Z Zheng  1 ,  I G Jennings  1 ,  R W Johnstone  2 ,  J Shortt  3 ,  S J Mountford  1 ,  M J Scanlon  1 ,  P E Thompson  4
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia.
  • 2. Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
  • 3. Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, 246 Clayton Road, Clayton, Victoria, Australia; Monash Haematology, Monash Health, 246 Clayton Road, Clayton, Victoria, Australia.
  • 4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, Australia. Electronic address: [email protected].
PMID: 32120339 DOI: 10.1016/j.ejmech.2020.112120
Abstract

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.

Keywords
BRD4; Bromodomain; Epigenetics; Fragment-based Drug Design; K-ac.
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