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Bioorg Med Chem Lett. 2015 Aug 1;25(15):2958-62. doi: 10.1016/j.bmcl.2015.05.036. Epub 2015 May 21.

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

Author information

1
Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States. Electronic address: qiaolin_deng@merck.com.
2
Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
3
Rahway Discovery Automated Synthesis and Purification, Merck Research Laboratories, Rahway, NJ 07065, United States.
4
Discovery Chemistry, ChemPartner, 998 Halei Road #5, Pudong New Area, Shanghai 201203, China.
5
Preformulation, Merck Research Laboratories, Rahway, NJ 07065, United States.
6
In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
7
Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
8
Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
9
Neuroscience Franchise Biology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.

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.

KEYWORDS:

Adenosine A(2A) receptor; Docking; MK-499; Superposition; Transformation; hERG

PMID:
26048804
DOI:
10.1016/j.bmcl.2015.05.036
[Indexed for MEDLINE]

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