Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors

Simon C. C. Lucas, Stephen J Atkinson, Chun-Wa Chung, Rob Davis, Laurie Gordon, Paola Grandi, James J R Gray, Thomas Grimes, Alexander Phillipou, Alex G Preston, Rab K Prinjha, Inmaculada Rioja, Simon Taylor, Nicholas C. O. Tomkinson, Ian Wall, Robert J Watson, James Woolven, Emmanuel H Demont

Research output: Contribution to journalArticlepeer-review

Abstract

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

Original languageEnglish
Pages (from-to)10711-10741
Number of pages31
JournalJournal of Medicinal Chemistry
Volume64
Issue number15
Early online date14 Jul 2021
DOIs
Publication statusPublished - 12 Aug 2021

Keywords

  • amides
  • rodent models
  • bromo and extra-terminal domain (BET)
  • bromodomains
  • pan-BET inhibitors
  • rat
  • dog
  • pharmacokinetics

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