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. 2013 Dec 1;23(23):6459-62.
doi: 10.1016/j.bmcl.2013.09.046. Epub 2013 Sep 25.

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  1 , 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 Ogden, Rosa Maria A Simmons, Douglas R Stack, Robert E Stratford, Mark A Winter, Zhipei Wu, Paul L Ornstein
Affiliations

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 et al. Bioorg Med Chem Lett. .

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.

Keywords: Decahydroisoquinolines; GluA2; GluK1 antagonists; Pain; Prodrug.

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