High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors.
The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 μM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.
Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. scott_wolkenberg@merck.com
Scott E
SE
Wolkenberg
Zhijian
Z
Zhao
James J
JJ
Mulhearn
Scott T
ST
Harrison
John M
JM
Sanders
Matthew J
MJ
Cato
Aneta
A
Jovanovska
Jacqueline
J
Panigel
Sean P
SP
Cook
Darrell A
DA
Henze
Stefanie A
SA
Kane
George D
GD
Hartman
James C
JC
Barrow
D062565:Acid Sensing Ion Channels; D000818:Animals; D055808:Drug Discovery; D055724:Electrophysiological Phenomena; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments; D051381:Rats; D054852:Small Molecule Libraries; D015222:Sodium Channels
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D015222:Sodium Channels