High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

Scott E Wolkenberg; Zhijian Zhao; James J Mulhearn; Scott T Harrison; John M Sanders; Matthew J Cato; Aneta Jovanovska; Jacqueline Panigel; Sean P Cook; Darrell A Henze; Stefanie A Kane; George D Hartman; James C Barrow

doi:10.1016/j.bmcl.2010.12.115

High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

Bioorg Med Chem Lett. 2011 May 1;21(9):2646-9. doi: 10.1016/j.bmcl.2010.12.115. Epub 2010 Dec 28.

Authors

Scott E Wolkenberg¹, Zhijian Zhao, James J Mulhearn, Scott T Harrison, John M Sanders, Matthew J Cato, Aneta Jovanovska, Jacqueline Panigel, Sean P Cook, Darrell A Henze, Stefanie A Kane, George D Hartman, James C Barrow

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. scott_wolkenberg@merck.com

PMID: 21257308
DOI: 10.1016/j.bmcl.2010.12.115

Abstract

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.

MeSH terms

Acid Sensing Ion Channels
Animals
Drug Discovery*
Electrophysiological Phenomena*
Molecular Structure
Nerve Tissue Proteins / antagonists & inhibitors*
Peptide Fragments
Rats
Small Molecule Libraries
Sodium Channels

Substances

ASIC3 protein, rat
Acid Sensing Ion Channels
Nerve Tissue Proteins
Peptide Fragments
Small Molecule Libraries
Sodium Channels