Identification of a series of n-methylpyridine-2-carboxamides as potent and selective inhibitors of the second bromodomain (BD2) of the bromo and extra terminal domain (BET) proteins

DOI: 10.1021/acs.jmedchem.0c02155

Authors: Lee A. Harrison (GlaxoSmithKline) , Stephen J. Atkinson (GlaxoSmithKline) , Anna Bassil (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , James R. J. Gray (GlaxoSmithKline) , Etienne Levernier (GlaxoSmithKline) , Antonia Lewis (GlaxoSmithKline) , David Lugo (GlaxoSmithKline) , Cassie Messenger (GlaxoSmithKline) , Anne-Marie Michon (GlaxoSmithKline) , Darren J. Mitchell (GlaxoSmithKline) , Alex Preston (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Inmaculada Rioja (GlaxoSmithKline) , Jonathan T. Seal (GlaxoSmithKline) , Simon Taylor (GlaxoSmithKline) , Ian D. Wall (GlaxoSmithKline) , Robert J. Watson (GlaxoSmithKline) , James M. 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: Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.

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

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 21/07/2021 09:45

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)