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

DOI: 10.1021/acs.jmedchem.1c00344

Authors: Simon C. C. Lucas (GlaxoSmithKline) , Stephen J. Atkinson (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Rob Davis (GlaxoSmithKline) , Laurie Gordon (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , James J. R. Gray (GlaxoSmithKline) , Thomas Grimes (GlaxoSmithKline) , Alexander Phillipou (GlaxoSmithKline) , Alex G. Preston (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Inmaculada Rioja (GlaxoSmithKline) , Simon Taylor (GlaxoSmithKline) , Nicholas C. O. Tomkinson (University of Strathclyde) , Ian Wall (GlaxoSmithKline) , Robert J. Watson (GlaxoSmithKline) , James Woolven (GlaxoSmithKline) , Emmanuel H. Demont (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2021

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.

Journal Keywords: Amides; Rodent models; Inhibitors; Solubility; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 28/07/2021 09:35

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)