Referenced in: none

Automatically associated channels: Kv11.1

Title: Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists.

Authors: Qiaolin Deng, Yeon-Hee Lim, Rajan Anand, Younong Yu, Jae-Hun Kim, Wei Zhou, Junying Zheng, Paul Tempest, Dorothy Levorse, Xiaoping Zhang, Scott Greene, Deborra Mullins, Chris Culberson, Brad Sherborne, Eric M Parker, Andrew Stamford, Amjad Ali

Journal, date & volume: Bioorg. Med. Chem. Lett., 2015 Aug 1 , 25, 2958-62

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26048804

Abstract
Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A 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.