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

Lucas, Simon C. C. and Atkinson, Stephen J and Chung, Chun-Wa and Davis, Rob and Gordon, Laurie and Grandi, Paola and Gray, James J R and Grimes, Thomas and Phillipou, Alexander and Preston, Alex G and Prinjha, Rab K and Rioja, Inmaculada and Taylor, Simon and Tomkinson, Nicholas C. O. and Wall, Ian and Watson, Robert J and Woolven, James and Demont, Emmanuel H (2021) Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors. Journal of Medicinal Chemistry, 64 (15). pp. 10711-10741. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.1c00344)

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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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