2. Academic Validation
  3. GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy

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.
Jose A Martinez-Perez 1,  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 Mattiuz,  Ann Marie L Ogden,  Rosa Maria A Simmons,  Douglas R Stack,  Robert E Stratford,  Mark A Winter,  Zhipei Wu,  Paul L Ornstein
Affiliations

Affiliation

  • 1 Centro de Investigación Lilly, Avda. de la Industria, 30, 28108 Alcobendas, Madrid, Spain. Electronic address: Martinez-Perez_Jose_A@Lilly.com.
PMID: 24140446 DOI: 10.1016/j.bmcl.2013.09.045
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.

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