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.
Scott E Wolkenberg  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. [email protected]
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.