Use of molecular modeling aided design to dial out hERG liability in adenosine A2A receptor antagonists

Abstract Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A 2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with p K a calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A 2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.