Use of molecular modeling aided design to dial out hERG liability in adenosine A2A receptor antagonists. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Deng, Qiaolin; Lim, Yeon-Hee; Anand, Rajan; Yu, Younong; Kim, Jae-hun; Zhou, Wei; Zheng, Junying; Tempest, Paul; Levorse, Dorothy; Zhang, Xiaoping; Greene, Scott; Mullins, Deborra; Culberson, Chris; Sherborne, Brad; Parker, Eric M.; Stamford, Andrew; Ali, Amjad
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 15(2015)
• Page Start: 2958
• Page End: 2962
• Publication Date: 2015-08-01
• Subjects: Adenosine A2A receptor -- hERG -- MK-499 -- Docking -- Superposition -- Transformation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.05.036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 p K a 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.