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

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.