GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: In vitro profile and in vivo analgesic efficacy

Jose A. Martinez-Perez, Smriti Iyengar, Harlan E. Shannon, David Bleakman, Andrew Alt, David K. Clawson, Brian M. Arnold, Michael G. Bell, Thomas J. Bleisch, Ana M. Castaño, Miriam Del Prado, Esteban Dominguez, Ana M. Escribano, Sandra A. Filla, Ken H. Ho, Kevin J. Hudziak, Carrie K. Jones, Ana Mateo, Brian M. Mathes, Edward L. MattiuzAnn Marie L. Ogden, Rosa Maria A. Simmons, Douglas R. Stack, Robert E. Stratford, Mark A. Winter, Zhipei Wu, Paul L. Ornstein

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.

Original languageEnglish (US)
Pages (from-to)6463-6466
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Keywords

  • Acid isoster
  • Decahydroisoquinolines
  • GluK1 antagonists
  • Pain
  • Prodrug

ASJC Scopus subject areas

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

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