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. Ogden & 6 others Rosa Maria A. Simmons, Douglas R. Stack, Robert Stratford Jr., Mark A. Winter, Zhipei Wu, Paul L. Ornstein

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Fingerprint

Prodrugs
Derivatives
Pain
Benzoic Acid
Structure-Activity Relationship
Oral Administration
Substitution reactions
Amino Acids

Keywords

  • Decahydroisoquinolines
  • GluA2
  • GluK1 antagonists
  • Pain
  • Prodrug

ASJC Scopus subject areas

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

Cite this

GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models. / Martinez-Perez, Jose A.; Iyengar, Smriti; Shannon, Harlan E.; Bleakman, David; Alt, Andrew; Arnold, Brian M.; Bell, Michael G.; Bleisch, Thomas J.; Castaño, Ana M.; Del Prado, Miriam; Dominguez, Esteban; Escribano, Ana M.; Filla, Sandra A.; Ho, Ken H.; Hudziak, Kevin J.; Jones, Carrie K.; Mateo, Ana; Mathes, Brian M.; Mattiuz, Edward L.; Ogden, Ann Marie L.; Simmons, Rosa Maria A.; Stack, Douglas R.; Stratford Jr., Robert; Winter, Mark A.; Wu, Zhipei; Ornstein, Paul L.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 23, 01.12.2013, p. 6459-6462.

Research output: Contribution to journalArticle

Martinez-Perez, JA, Iyengar, S, Shannon, HE, Bleakman, D, Alt, A, Arnold, BM, Bell, MG, Bleisch, TJ, Castaño, AM, Del Prado, M, Dominguez, E, Escribano, AM, Filla, SA, Ho, KH, Hudziak, KJ, Jones, CK, Mateo, A, Mathes, BM, Mattiuz, EL, Ogden, AML, Simmons, RMA, Stack, DR, Stratford Jr., R, Winter, MA, Wu, Z & Ornstein, PL 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, vol. 23, no. 23, pp. 6459-6462. https://doi.org/10.1016/j.bmcl.2013.09.046
Martinez-Perez, Jose A. ; Iyengar, Smriti ; Shannon, Harlan E. ; Bleakman, David ; Alt, Andrew ; Arnold, Brian M. ; Bell, Michael G. ; Bleisch, Thomas J. ; Castaño, Ana M. ; Del Prado, Miriam ; Dominguez, Esteban ; Escribano, Ana M. ; Filla, Sandra A. ; Ho, Ken H. ; Hudziak, Kevin J. ; Jones, Carrie K. ; Mateo, Ana ; Mathes, Brian M. ; Mattiuz, Edward L. ; Ogden, Ann Marie L. ; Simmons, Rosa Maria A. ; Stack, Douglas R. ; Stratford Jr., Robert ; Winter, Mark A. ; Wu, Zhipei ; Ornstein, Paul L. / GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 23. pp. 6459-6462.
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AU - Bleakman, David

AU - Alt, Andrew

AU - Arnold, Brian M.

AU - Bell, Michael G.

AU - Bleisch, Thomas J.

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AU - Del Prado, Miriam

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AU - Mattiuz, Edward L.

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AU - Simmons, Rosa Maria A.

AU - Stack, Douglas R.

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AU - Winter, Mark A.

AU - Wu, Zhipei

AU - Ornstein, Paul L.

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