title: Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists.
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.
authors.affiliation: Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States. Electronic address: qiaolin_deng@merck.com.
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Lim
authors.affiliation: Rahway Discovery Automated Synthesis and Purification, Merck Research Laboratories, Rahway, NJ 07065, United States.
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.affiliation: Rahway Discovery Automated Synthesis and Purification, Merck Research Laboratories, Rahway, NJ 07065, United States.
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Rahway Discovery Automated Synthesis and Purification, Merck Research Laboratories, Rahway, NJ 07065, United States.
authors.forename: Jae-hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Discovery Chemistry, ChemPartner, 998 Halei Road #5, Pudong New Area, Shanghai 201203, China.
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
authors.affiliation: Preformulation, Merck Research Laboratories, Rahway, NJ 07065, United States.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Levorse
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Greene
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Deborra
authors.initials: D
authors.lastname: Mullins
authors.affiliation: Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Culberson
authors.affiliation: Structural Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Brad
authors.initials: B
authors.lastname: Sherborne
authors.affiliation: Neuroscience Franchise Biology, Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.affiliation: Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stamford
authors.affiliation: Rahwy Discovery Chemistry, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, United States.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D001578:Benzopyrans; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D011799:Quinazolines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C087257:L 706000
keywords: Adenosine A(2A) receptor; Docking; MK-499; Superposition; Transformation; hERG