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

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6463-6. doi: 10.1016/j.bmcl.2013.09.045. Epub 2013 Sep 24.

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.

Keywords: Acid isoster; Decahydroisoquinolines; GluK1 antagonists; Pain; Prodrug.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Amino Acid Sequence
  • Animals
  • Disease Models, Animal
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Male
  • Molecular Sequence Data
  • Pain / drug therapy*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Receptors, Kainic Acid / chemistry
  • Structure-Activity Relationship
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*

Substances

  • Gluk1 kainate receptor
  • Isoquinolines
  • Prodrugs
  • Receptors, Kainic Acid
  • Tetrazoles
  • dasolampanel etibutil