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 Barrow

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2646-2649
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number9
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Acid Sensing Ion Channel Blockers
Acid Sensing Ion Channels
Electrophysiology
Pharmacokinetics
Rats
Physical properties
Ligands
Pain
Therapeutics

Keywords

  • Acid-sensing ion channel 3
  • Electrophysiology
  • Fragment screening

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

High concentration electrophysiology-based fragment screen : Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors. / Wolkenberg, Scott E.; Zhao, Zhijian; Mulhearn, James J.; Harrison, Scott T.; Sanders, John M.; Cato, Matthew J.; Jovanovska, Aneta; Panigel, Jacqueline; Cook, Sean P.; Henze, Darrell A.; Kane, Stefanie A.; Hartman, George D.; Barrow, James.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 9, 01.05.2011, p. 2646-2649.

Research output: Contribution to journalArticle

Wolkenberg, SE, Zhao, Z, Mulhearn, JJ, Harrison, ST, Sanders, JM, Cato, MJ, Jovanovska, A, Panigel, J, Cook, SP, Henze, DA, Kane, SA, Hartman, GD & Barrow, J 2011, 'High concentration electrophysiology-based fragment screen: Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 9, pp. 2646-2649. https://doi.org/10.1016/j.bmcl.2010.12.115
Wolkenberg, Scott E. ; Zhao, Zhijian ; Mulhearn, James J. ; Harrison, Scott T. ; Sanders, John M. ; Cato, Matthew J. ; Jovanovska, Aneta ; Panigel, Jacqueline ; Cook, Sean P. ; Henze, Darrell A. ; Kane, Stefanie A. ; Hartman, George D. ; Barrow, James. / High concentration electrophysiology-based fragment screen : Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 9. pp. 2646-2649.
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