GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models

Jose A. Martinez-Perez, Smriti Iyengar, Harlan E. Shannon, David Bleakman, Andrew Alt, 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. OgdenRosa Maria A. Simmons, Douglas R. Stack, Robert E. Stratford, Mark A. Winter, Zhipei Wu, Paul L. Ornstein

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.

Original languageEnglish (US)
Pages (from-to)6459-6462
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Keywords

  • Decahydroisoquinolines
  • GluA2
  • 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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  • Cite this

    Martinez-Perez, J. A., Iyengar, S., Shannon, H. E., Bleakman, D., Alt, A., Arnold, B. M., Bell, M. G., Bleisch, T. J., Castaño, A. M., Del Prado, M., Dominguez, E., Escribano, A. M., Filla, S. A., Ho, K. H., Hudziak, K. J., Jones, C. K., Mateo, A., Mathes, B. M., Mattiuz, E. L., ... Ornstein, P. L. (2013). GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models. Bioorganic and Medicinal Chemistry Letters, 23(23), 6459-6462. https://doi.org/10.1016/j.bmcl.2013.09.046