2. Academic Validation
  3. Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors

Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors

  • J Med Chem. 2021 Aug 12;64(15):10711-10741. doi: 10.1021/acs.jmedchem.1c00344.
Simon C C Lucas,  Stephen J Atkinson,  Chun-Wa Chung,  Rob Davis,  Laurie Gordon,  Paola Grandi 1,  James J R Gray,  Thomas Grimes,  Alexander Phillipou,  Alex G Preston,  Rab K Prinjha,  Inmaculada Rioja,  Simon Taylor,  Nicholas C O Tomkinson 2,  Ian Wall,  Robert J Watson,  James Woolven,  Emmanuel H Demont
Affiliations

Affiliations

  • 1 IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 2 WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 259 Cathedral Street, Glasgow G1 1XL, U.K.
PMID: 34260229 DOI: 10.1021/acs.jmedchem.1c00344
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.

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